Nitrogen containing heterobicycles as factor Xa inhibitors

ABSTRACT

The present application describes nitrogen containing heterobicyclics and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.

This application is a divisional application of U.S. application Ser.No. 09/898,279, filed Jul. 3, 2001, now U.S. Pat. No. 6,673,810, whichis a divisional application of U.S. application Ser. No. 09/470,326,filed Dec. 22, 1999, now U.S. Pat. No. 6,413,980, which claims benefitof U.S. Provisional Application No. 60/113,628, filed on Dec. 23, 1998and U.S. Provisional Application No. 60/127,633, filed on Apr. 02, 1999,the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates generally to nitrogen containing heterobicycles,which are inhibitors of trypsin-like serine protease enzymes, especiallyfactor Xa, pharmaceutical compositions containing the same, and methodsof using the same as anticoagulant agents for treatment and preventionof thromboembolic disorders.

BACKGROUND OF THE INVENTION

WO94/20460 describes angiotensin II compounds of the following formula:

wherein X can be a number of substituents and Het can be anitrogen-containing heterobicycle. However, WO94/20460 does not suggestFactor Xa inhibition or exemplify compounds like those of the presentinvention.

WO96/12720 describes phosphodiesterase type IV and TNF productioninhibitors of the following formula:

wherein X can be oxygen and R² and R³ can a number of substituentsincluding heterocycle, heterocycloalkyl, and phenyl. However, thepresently claimed compounds do not correspond to the compounds ofWO96/12720. Furthermore, WO96/12720 does not suggest Factor Xainhibition.

WO98/52948 describes inhibitors of ceramide-mediated signaltransduction. One of the types of inhibitors described is of thefollowing formula:

wherein Y₁ can be N—R₆, R₆ can be unsubstituted aryl-alkyl orunsubstituted heterocyclic-alkyl and R₁ can be a substituted aryl group.WO98/52948 does not mention factor Xa inhibition or show compounds likethose of the present invention.

U.S. Pat. Nos. 3,365,459 and 3,340,269 illustrates anti-inflammatoryinhibitors of the following formula:

wherein A is 2-3 carbon atoms, X can be 0, and R¹ and R³ can besubstituted or unsubstituted aromatic groups. Neither of these patents,however, exemplify compounds of the present invention.

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617-629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are neededas potentially valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus desirable to discover new factor Xainhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelnitrogen containing heterobicycles that are useful as factor Xainhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating thromboembolic disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

It is another object of the present invention to provide novel bicycliccompounds for use in therapy.

It is another object of the present invention to provide the use ofnovel bicyclic compounds for the manufacture of a medicament for thetreatment of a thromboembolic disorder.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed bicyclic compounds, or pharmaceuticallyacceptable salt or prodrug forms thereof, are effective factor Xainhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novelcompound selected from the group:

-   or a stereoisomer or pharmaceutically acceptable salt thereof,    wherein compounds of the above formulas are substituted with 0-2 R³;-   G is a group of formula I or II:-   ring D is selected from —(CH₂)₃—, —(CH₂)₄—, —CH₂N═CH—, —CH₂CH₂N═CH—,    and a 5-6 membered aromatic system containing from 0-2 heteroatoms    selected from the group N, O, and S, provided that from 0-1 O and S    atoms are present;-   ring D, when present, is substituted with 0-2 R;-   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and    pyridazinyl, substituted with 0-1 R;-   R is selected from Cl, F, Br, I, OH, C₁₋₃ alkoxy, NH₂, NH(C₁₋₃    alkyl), N(C₁₋₃ alkyl)₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃    alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃ alkyl), and CH₂CH₂N(C₁₋₃ alkyl)₂;-   alternatively, ring D is absent;-   when ring D is absent, ring E is selected from phenyl, pyridyl,    pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted    with R″ and R′;-   R″ is selected from F, Cl, Br, I, OH, C₁₋₃ alkoxy, CN, C(═NR⁸)NR⁷R⁹,    NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), C(O)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷R⁸, SH, C₁₋₃    alkyl-S, S(O)R^(3b), S(O)₂R^(3a), S(O)₂NR²R^(2a), and OCF₃;-   R′ is selected from H, F, Cl, Br, I, SR³, CO₂R³, NO₂, (CH₂)_(t)OR³,    C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;-   alternatively, R″ and R′ combine to form methylenedioxy or    ethylenedioxy;-   Z is N or CR^(1a);-   Z¹ is S, O, or NR³;-   Z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R³, and    S(O)_(p)R^(3c);-   R^(1a) is selected from H, —(CH₂)_(r)—R¹′, —CH═CH—R¹′, NHCH₂R¹″,    OCH₂R¹″, SCH₂R¹″, NH(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and    S(CH₂)₂(CH₂)_(t)R¹′;-   R¹′ is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO,    (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R²,    (CF₂)_(r)CO₂R²C, S(O)_(p)R^(2b), NR²(CH₂)_(r)OR²,    C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)R³, NR²C(O)NHR^(2b),    NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a),    C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclic    residue substituted with 0-2 R^(4a), and 5-10 membered heterocyclic    system containing from 1-4 heteroatoms selected from the group    consisting of N, O, and S substituted with 0-2 R^(4a);-   R¹′ is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);-   R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,    C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), a C₃₋₆    carbocyclic-CH₂— residue substituted with 0-2 R^(4b), and 5-6    membered heterocyclic system containing from 1-4 heteroatoms    selected from the group consisting of N, O, and S substituted with    0-2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl,    benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and    5-6 membered heterocyclic system containing from 1-4 heteroatoms    selected from the group consisting of N, O, and S substituted with    0-2 R^(4b);    -   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy,        C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with        0-2 R^(4b), and 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from the group consisting of N, O, and        S substituted with 0-2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2    R^(4b), and 5-6 membered heterocyclic system containing from 1-4    heteroatoms selected from the group consisting of N, O, and S    substituted with 0-2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0-2 R^(4b) and    containing from 0-1 additional heteroatoms selected from the group    consisting of N, O, and S;-   R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;-   R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and    phenyl;-   R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and    phenyl;-   R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, and phenyl;-   A is selected from:    -   C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and    -   5-10 membered heterocyclic system containing from 1-4        heteroatoms selected from the group consisting of N, O, and S        substituted with 0-2 R⁴;-   B is selected from:    -   Y, X-Y, C(═NR²)NR²R^(2a), NR²C(═NR²)NR²R^(2a),    -   C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and    -   5-10 membered heterocyclic system containing from 1-4        heteroatoms selected from the group consisting of N, O, and S        substituted with 0-2 R^(4a);-   X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b)) (CH₂)_(t)—,    —C(O)—, —C(═NR¹″)—, —CR²(NR¹¹R²)—, —CR²(OR²)—, —CR²(SR²)—,    —C(O)CR²R^(2a), —CR²R^(2a)C(O), —S(O)_(p)—, —S(O), CR²R^(2a)—,    —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—,    —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—,    —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²,    —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—,    NR²CR²R^(2a)—, —CR²R^(2a)NR², 0, —CR²R^(2a)O—, and —OCR²R^(2a)—;-   Y is selected from:    -   CH₂NR²R^(2a);    -   CH₂CH₂NR²R^(2a);    -   C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and    -   5-10 membered heterocyclic system containing from 1-4        heteroatoms selected from the group consisting of N, O, and S        substituted with 0-2 R^(4a);-   R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl,    Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a),    (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),    C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC    (═NR²) NR²R^(2a), SO₂NR²R^(2a), NR² SO₂NR²R^(2a), NR² SO₂₂—C₁₋₄    alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R¹, OCH₂R¹′, SCH₂R¹,    N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂) 2 (CH₂)_(t)R¹′;-   alternatively, one R⁴ is a 5-6 membered aromatic heterocycle    containing from 1-4 heteroatoms selected from the group consisting    of N, O, and S;-   R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,    (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl,    —CN, NO₂, (CH₂)_(r)NR²R²&, (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), (CH₂), N═CHOR³, C(O)NH(CH₂)₂NR²R^(2a),    NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄    alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;-   alternatively, one R^(4a) is a 5-6 membered aromatic heterocycle    containing from 1-4 heteroatoms selected from the group consisting    of N, O, and S substituted with 0-1 R⁵;-   R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F,    Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a),    (CH₂)_(r)C(O)R³, (CH₂)_(r)C (O)OR³C, NR³C(O)R^(3a), C(O)NR³R^(3a),    NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃,    NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,    and (CF₂)_(r)CF₃;-   R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl    substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;-   R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo,    C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),    NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂,    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₁₄ alkyl;-   R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆    alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl,    C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄    alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄    alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and    phenyl C₁₋₄ alkoxycarbonyl;-   R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and    (CH₂)_(n)-phenyl;-   alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered    saturated, ring which contains from 0-1 additional heteroatoms    selected from the group consisting of N, O, and S;-   R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and    (CH₂)_(n)-phenyl;-   n, at each occurrence, is selected from 0, 1, 2, and 3;-   m, at each occurrence, is selected from 0, 1, and 2;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, and 3;-   s, at each occurrence, is selected from 0, 1, and 2; and,-   t, at each occurrence, is selected from 0, 1, 2, and 3.

[2] In a preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from the group:

-   wherein compounds of the above formulas are substituted with 0-2 R³;-   G is selected from the group:-   A is selected from one of the following carbocyclic and heterocyclic    systems which are substituted with 0-2 R⁴;    -   phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,        morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,        1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,        1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,        1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,        benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,        benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and        isoindazolyl;-   B is selected from: Y, X-Y, C(═NR²)NR²R^(2a), and    NR²C(═NR²)NR²R^(2a);-   X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—,    —CR²(NR²R^(2a))-, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—,    —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—,    —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—,    —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;-   Y is CH₂NR²R^(2a) or CH₂CH₂NR²R^(2a);-   alternatively, Y is selected from one of the following carbocyclic    and heterocyclic systems that are substituted with 0-2 R^(4a);    -   cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl,        piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,        thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,        isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,        1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,        1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,        1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,        benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,        benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and        isoindazolyl;-   alternatively, Y is selected from the following bicyclic heteroaryl    ring systems:

K is selected from O, S, and N; and,

-   s is 0.

[3] In a more preferred embodiment, the present invention provides anovel compound, wherein the compound is selected from the group:

-   wherein compounds of the above formulas are substituted with 0-2 R³;-   G is selected from the group:

[4] In an even more preferred embodiment, the present invention providesa novel compound, wherein:

-   G is selected from:-   [5] In a still more preferred embodiment, the present invention    provides a novel compound, wherein;-   A is selected from phenyl, pyridyl, and pyrimidyl, and is    substituted with 0-2 R⁴; and,-   B is selected from X-Y, phenyl, pyrrolidino, morpholino,    1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);-   R², at each occurrence, is selected from H, CH₃, CH₂CH₃,    cyclopropylmethyl, cyclobutyl, and cyclopentyl;-   R^(2a), at each occurrence, is H or CH₃;-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form pyrrolidine substituted with 0-2    R^(4b);-   R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo,    C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;-   R^(4a) is selected from C₁₋₄ alkyl, CF₃, (CH₂)_(r)OR²,    (CH₂)_(r)NR²R^(2a), S(O)_(p)R⁵, SO₂NR²R^(2a), and    1-CF₃-tetrazol-2-yl;-   R^(4b), at each occurrence, is selected from H, CH₃, and OH;-   R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl,    and benzyl;-   X is CH₂ or C(O);-   Y is selected from pyrrolidino and morpholino; and,-   r, at each occurrence, is selected from 0, 1, and 2.

[6] In a further preferred embodiment, the present invention provides anovel compound, wherein;

-   A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl,    2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl,    2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,-   B is selected from the group: 2-(aminosulfonyl)phenyl,    2-(methylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl,    2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl,    2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl,    2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl,    2-(N-(cyclopropylmethyl)aminomethyl)phenyl,    2-(N-(cyclobutyl)aminomethyl)phenyl,    2-(N-(cyclopentyl)aminomethyl)phenyl, and    2-(N-(3-hydroxypyrrdlidinyl)methyl)phenyl.

[7] In an even further preferred embodiment, the present inventionprovides a novel compound selected from:

-   1-[4-Methoxyphenyl]-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4-dihydropyrazolo-[4,3-d]-pyrimidine-5,7-dione;-   1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-6-[12-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl-3-(aminocarbonyl)-6-[2-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-6-(2′-aminosulfonyl-[1,1′-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one-3-carboxylic    acid;-   1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-(2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-cyano-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(aminomethyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[4-(2-methylimidazol-1′-yl)phenyl)-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl)-3-(aminocarbonyl)-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-cyano-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2-fluoro-4-(2-dimethylaminomethylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[2-Aminomethylphenyl]-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminoiminomethylphenyl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[2-Aminomethylphenyl]-3-methyl-6-(2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[4-Methoxyphenyl]-3-cyano-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-cyano-5-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[2-Aminomethylphenyl]-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2′-aminosulfonyl-(1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one,-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[4-(1-methylimidazol-2′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)    6-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2′-(3-(R)-hydroxy-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-(N-formylaminomethyl)-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-[1,1′)-biphen-4-yl]-1,6-dihydropyrazolo-(4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[(1,1]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl)-3-trifluoromethyl-7-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-(3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-isopropylaminomethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-(1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-51-yl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-7-[2′-N-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-isopropylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-(2-dimethylaminomethylimidazol-1′-yl)-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-(imidazol-1′-yl)-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[2-Aminomethylphenyl]-3-trifluoromethyl-7-(2′-methylsulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(3-(S)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-isopropylaminomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-(3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;-   1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-aminosulfonyl-3-fluoro-[1,11]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-[1,1]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-(2′-N,N-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-isopropylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl)-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-6-[2′-N-(2-methylimidazol-1-yl)methyl-3-fluoro-[1,1′)-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N-pyrrolidinomethyl-3-fluoro-[1,1′]-biphen-4-yl)-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-51-yl]-3-trifluoromethyl-6-[2′-oximinomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[4-Methoxyphenyl]-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-[(tetrazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[4-Methoxyphenyl]-3-[(tetrazol-2-yl)methyl]-5-methyl-6-[(21-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-isopropylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(4,5-dihydroimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-(cyclopropylmethyl)aminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(N-methyl-N-isopropyl)aminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′)-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(S)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,    4, 5, 6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N-(pyrrolindinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N-(morpholino)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[(3′-N-dimethylaminomethyl)-3-fluoro-[1,11]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[(3′-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(3′-N-pyrrolidinylmethyl)-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(3′-N-dimethylaminomethyl)-[1,1]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-benzimidazol-1′-yl-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;-   1-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;-   1-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(21′-N-dimethylaminomethyl)-3-fluoro-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;-   1-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N-(R)-3-hydroxypyrrolidinylmethyl)-3-fluoro-[1,1′)-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-clazepin-8-one;-   1-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N—(R)-3-hydroxypyrrolidinylmethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;-   1-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N-dimethylaminomethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(2′-N-pyrrolidinylmethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;-   1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(2′-N,N-dimethylaminomethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;-   1[4-Methoxyphenyl]-3-trifluoromethyl-6-[(4-aminomethyl)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridin-7-one;-   1-[3-Aminomethylphenyl]-3-methyl-6-[(2′-N-((3-(S)-hydroxy)pyrrolidinyl)    methyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminomethylphenyl]-3-methyl-6-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)]-1,    4, 5, 6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[(3-fluoro-2′-N-(3    (S)-hydroxy)pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[(3-fluoro-2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-[1-Aminoisoquinolin-7′-yl]-3-trifluoromethyl-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(2-(dimethylaminomethyl)imidazol-1-yl)-2-fluorophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;-   1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[4-(2-(dimethylaminomethyl)imidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;    and,-   1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(2-(dimethylaminomethyl)imidazol-1′-yl)-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;    or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating or preventing a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt form thereof.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. C₁₋₁₀ alkyl, is intended to includeC₁, C₂, C3, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl”is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more halogen (for example—C_(v)F_(w) wherev=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are notlimited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, andpentachloroethyl. “Alkoxy” represents an alkyl group as defined abovewith the indicated number of carbon atoms attached through an oxygenbridge. C₁₋₁₀ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇,C₈, C₉, and C₁₀ alkoxy groups. Examples of alkoxy include, but are notlimited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to includesaturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.C₃₋₇ cycloalkyl is intended to include C₃, C₄, Cs, C₆, and C₇ cycloalkylgroups. Alkenyl″ is intended to include hydrocarbon chains of eitherstraight or branched configuration and one or more unsaturatedcarbon—carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₁₀ alkenyl is intended to include C₂,C₃, C₄, C₅, C₆, C₇, Cs, Cg, and C₁₀ alkenyl groups. “Alkynyl” isintended to include hydrocarbon chains of either straight or branchedconfiguration and one or more triple carbon—carbon bonds that may occurin any stable point along the chain, such as ethynyl and propynyl. C₂₋₁₀Alkynyl is intended to include C₂, C3, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue, is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1. Asused herein, the term “aromatic heterocyclic system” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, NH, O and S. It is to be notedthat total number of S and O atoms in the aromatic heterocycle is notmore than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc .. . ) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.Preferred prodrugs are amidine prodrugs wherein D is C(═NR⁷)NH₂ or itstautomer C(═NH)NHR⁷ and R⁷ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀aryloxy, C₁₋₄ alkoxycarbonyl, C_(6-1O) aryloxycarbonyl, C_(6-1O)arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are whereR⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, andmethylcarbonyloxymethoxycarbonyl.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Substituted” is intended to indicate that one or more hydrogens on theatom indicated in the expression using “substituted” is replaced with aselection from the indicated group(s), provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O) group, then2 hydrogens on the atom are replaced.

”Therapeutically effective amount⇄ is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit factor Xa. The combination ofcompounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,22:27-55, occurs when the effect (in this case, inhibition of factor Xa)of the compounds when administered in combination is greater than theadditive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased antiviral effect, or some other beneficialeffect of the combination compared with the individual components.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

The compounds of the present invention represented by Formula I consistof a group “D-E-G-(CH₂)_(s)-” and a group “-A-B” attached to a [5,6]- or[5,7]-heterobicyclic core structure of varying composition. Thefive-membered ring can be pyrazole, triazole, isoxazole or isothiazoleand this ring can be fused to a variety of six- or seven membered ringsincluding but not limited to piperidinone, pyridinone, pyrimidinone,pyrimidinedione, pyranone, diazepinone, diazepinedione. The followingdiscussion and schemes will describe methods for the syntheses of theheterobicyclic cores and attachment to the groups “G-(CH₂)_(s)-” and“-A-B”.

The 4-aminopyrazole-5-carboxylate V is a useful intermediate for thepreparation of many of the pyrazole fused compounds of Formula I whereinthe “G-(CH₂),-” residue is attached to a nitrogen atom of the pyrazole(Scheme I). This intermediate can be prepared in a variety of ways fromhydrazines I. Hydrazines I are readily available starting materials.Aromatic hydrazines (G is aryl, s=0) are conveniently prepared from thecorresponding aniline by diazotization with NaNO₂ in acidic mediafollowed by reduction of the resulting diazonium ion with a suitablereducing agent, with SnCl₂ being a preferred reagent. Non-aromatichydrazines represented by I are readily prepared by a variety ofmethods, such as by displacement of a suitable halogen compound withhydrazine or with a protected hydrazine followed by deprotection.Condensation of hydrazines I with a suitable hemiacetal or aldehydefollowed by halogenation with NBS or NCS leads to hydrazidoyl halidesII. Alternatively, the hydrazines I can be acylated with an acidchloride and converted to hydrazidoyl halides II by carbontetrahalide/triphenylphosphine. The hydrazidoyl halides II are versatileintermediates for pyrazole synthesis (Shawali, A. S.; et. al. J. Het.Chem. 1980, 17, 833). The halide can be displaced with cyanide ion toafford cyanide III. Cyano compounds of this type (where G is aryl ands=0) can also be prepared more directly by diazotization of aniline IVfollowed by direct reaction with a cyano-containing active methylenecompound, where R^(1a) can include a variety of groups such as ester,ketone, cyano, trifluoromethyl, sulfone, aryl, etc. (Butler, R. N.; et.al. J. Chem. Soc. Chem. Commun. 1992, 20, 1481). Treatment of III with abromoacetate in the presence of a suitable base such as carbonate ortrialkylamine results in N-alkylation followed by ring closure to givethe 4-aminopyrazole-5-carboxylate V. Alternatively, treatment of II witha nitropyruvate in the presence of a base such as alkoxide provides a4-nitropyrazole by displacement of the halide followed by ring closureof the nitrogen onto the carbonyl group. Reduction of the nitro groupcan be accomplished by a variety of reducing agents, a preferred one ofwhich is SnCl₂, to give the 4-aminopyrazole-5-carboxylate V. Thehyrazidoyl halide II can also be reacted with a ketoester where R′represents a masked ester, preferably a 2-furyl residue, to give apyrazole-4-carboxylate VI. Ester hydrolysis, conversion to an acylazide, either via the acid chloride or anhydride, heating to generate anisocyanate via Curtius rearrangement, and finally treatment with wateraffords the 4-aminopyrazole VII. Alternatively, the amino can be maskedas an appropriate carbamate by using an alcohol instead of water in theCurtius rearrangement. When R′=2-furyl, the furan can be oxidativelycleaved under a variety of conditions, such as sodium periodate withcatalytic ruthenium trichloride, or KMnO₄, to afford a carboxylic acidwhich can be esterified to afford the 4-aminopyrazole-5-carboxylate V.

Another route to the 4-aminopyrazole V involves condensation of thehydrazine I with an appropriate diketone or monoprotected diketone toform a 3,5-disubstituted pyrazole in which the 5-substituent is acarboxylic ester. With proper choice of the G group, this pyrazole canbe selectively nitrated at the 4-position with nitrating agents such asnitric acid or ammonium nitrate/trifluoroacetic anhydride. Reduction ofthe nitro group under a variety of conditions, such as with tin (II)chloride or catalytic hydrogenation, affords the 4-aminopyrazole V. Thisroute can also be carried out using a diketone with a 2-furyl group as alatent carboxylate, giving initially a 3,5-disubstituted pyrazole inwhich the 5-substituent is the 2-furyl group. Oxidative cleavage of thefuryl group to a carboxylate, nitration of the pyrazole 4-position,esterification and nitro reduction then affords 4-aminopyrazole V. Itwill be recognized by those skilled in the art that the synthetic routechosen to V will depend on additional functionality present in themolecule of interest and the route may require additionalprotection/deprotection sequences as well as modifications in the orderof synthetic steps.

In Scheme II is shown how the 4-aminopyrazole-5-carboxylate V can beutilized to prepare a variety of structures described by Formula I wherethe A-B residue is connected to a nitrogen atom of the bicyclic core.The 4-amino group can be protected as a suitable carbamate (see Greeneand Wuts, Protective Groups in Organic Synthesis, Wiley and Sons, 1991)or as an azide group (NaNO₂, acid, NaN₃). In some cases it may not benecessary to protect the amino functionality, as will be recognized bythose skilled in the art. Unmasking of the ester residue involves eitherbasic hydrolysis (R=Me, Et), hydrogenolysis (R=Bn) or trifluoroaceticacid (R=t-Bu). Coupling of the resulting acid with the appropriate amineH₂N-A-B can be accomplished by a wide variety of methods known to thoseskilled in the art, including dicyclohexylcarbodiimide andN,N-dimethylaminopyridine, the mixed anhydride method, the BOP reagent,and many others. Alternatively, the amide bond can be formed directlyfrom the ester (R=Me, Et) by reacting the ester with an aluminum reagentprepared from the amine H₂N-A-B and trimethylaluminum. Deprotection ofthe amino group, if required, provides compounds VIII. Treating thisamino amide with carbonyl diimidazole or other phosgene equivalent, suchas triphosgene, provides pyrazolopyrimidinediones IX. Alternatively,aminocarboxylate V can be converted to pyrazolopyrimidinediones IX in asingle step by heating with an appropriate isocyanate OCN-A-B in thepresence of a base such as sodium hydride. Treating VIII with asubstituted bromoacetyl chloride or bromide in the presence of a basesuch as triethylamine affords the pyrazolodiazepinediones X. RefluxingVIII in the presence of formic acid provides the pyrazolopyrimidinonesXI (R³=H). Substituted derivatives XI can be obtained by refluxing VIIIin the presence of triethylorthoacetate (R³=Me) or other orthoesters.Reduction of XI with catalytic hydrogenation, sodium borohydride inacidic medium or other reducing agent can provide compounds of type XII.Additionally, V can be treated with a bromoacetate in the presence of abase such as carbonate or sodium hydride to provide XIII. Selectivehydrolysis of either ester of XIII followed by standard coupling withH₂N-A-B and subsequent heating affords compounds XIV, which areregioisomeric with X. Oxygen analogs of XIV are prepared by convertingthe amino group of V to a hydroxy group via a diazonium ion. Couplingwith the amine H₂N-A-B by any of a wide variety of procedures yields XV.O-alkylation of XV with a bromoacetate in the presence of a base such assodium hydride leads to XVI, the oxygen analogs of XIV. In the cases ofcompounds IX, X, XII and XIV the nitrogen atom can be furtherfunctionalized to provide additional analogs, such as by treating withmethyl iodide in the presence of a base to afford the N-methylderivatives.

The 4-aminopyrazole-5-carboxylate can be used to preparepyrazolopyranone and pyrazolopyridinone derivatives, in which the A-Bresidue is attached to a carbon atom of the bicyclic core, as shown inScheme III. N-protection of V as described previously can be followed bystraightforward conversion of the ester residue to an acid chloride.Treatment of this acid chloride with a zinc cuprate reagent derived fromBr—CH₂-A-B (A=aryl) will afford the ketone XVII after N-deprotection.Heating XVII with dimethylformamide dimethylacetal or with an orthoestercan provide the pyrazolopyridinone compounds XVIII. Conversion of the4-amino residue of XVII to a hydroxyl group via the diazonium ion willlead to XIX, which will provide the pyrazolopyranone derivatives XXunder similar cyclization conditions. Alternatively, treatment of theacid chloride XXI, obtained as described above where N-PG can representa carbamate protected nitrogen or can represent conversion of the aminogroup to an azide group as described previously, with a suitable enaminein the presence of a base such as triethylamine can afford the ketoneXXII. N-deprotection followed by heating will afford thepyrazolopyridinones XXIII (XVIII where R═H). Also, the ketone XVII canbe prepared from the cyano compound III by treatment with a suitablebromoketone in the presence of a base such as carbonate ortriethylamine. The required bromoketone is readily available by treatingan appropriate acid chloride with diazomethane followed by HBr. It willbe recognized by those skilled in the art that the syntheses of thecompounds described in Scheme III may require additionalprotection/deprotection steps or modifications in the order of carryingout the steps, depending on additional functionality present in thecompounds of interest.

Additional oxygen-containing bicyclic systems can be prepared as shownin Scheme IV. The 4-amino-5-carboxylate V can be converted to its4-hydroxy derivative via the diazonium ion to give XXIV. Esterdeprotection and amide bond formation with an appropriate H₂N-A-B asdescribed in Scheme II will afford the amide XXV. Alternatively, theamide bond can be formed directly from the ester by addition of thealuminum reagent derived from H₂N-A-B and trimethylaluminum. The4-hydroxy substituent can be easily protected if required by any of anumber of protecting groups, such as with t-butyldimethylsilyl ether(TBS), and then deprotected following amide bond formation. Treating thehydroxy amide XXV with carbonyl diimidazole or other phosgeneequivalent, such as triphosgene, can provide the bicyclic core XXVI.Heating XXV in the presence of paraformaldehyde in the presence of asuitable acid such as p-toluenesulfonic acid will provide XXVII (R³=H).Alternatively, XXV can be treated with dibromomethane in the presence ofa suitable base such as carbonate to afford XXVII (R³=H). Otheraldehydes and substituted dibromomethanes can provide substitutedderivatives of XXVII where R³ is not hydrogen.

Additional bicyclic system s in which the A-B residue is substituted ona carbon atom can be prepared as shown in Scheme V. N-protection of4-aminopyrazole-5-carboxylate V can be followed by manipulation of theester to afford an acid chloride or an N-methoxy-N-methyl amide.Addition of an enolate derived from RO₂CCH₂-A-B and a base such aslithium diisopropylamide or lithium hexamnethyldisilazide providesXXVIII. The N-methoxy-N-methyl amide is the preferred reaction partnerfor this addition, as this functionality prevents the formation ofoveraddition products. Alternatively, the enolate addition reactioncould be done on the ester as well. N-deprotection of the 4-aminosubstituent allows it to close onto the ester residue and provides thepyrazolopiperidinedione XXIX. Manipulation of the ester residue ofXXVIII can lead to XXX where X represents a suitable leaving group suchas a bromide or mesylate residue. A variety of methods can be utilizedfor the transformation of XXVIII to XXX, such as ketone protection,reduction of the ester to a primary alcohol, ketone deprotection andconversion of the primary alcohol to a bromide using CBr₄/PPh₃ or to amesylate using methanesulfonyl chloride and a base such astriethylamine. Alternatively, the ester can be hydrolyzed to the acidthat can be reduced to the primary alcohol with borane and converted toa leaving group as just described. N-deprotection liberates the 4-aminogroup, which provides compounds of structure XXXI upon heating ortreatment with base. The corresponding oxygen derivative is alsoavailable from XXVIII. N-deprotection, diazotization with NaNO₂ inacidic medium and treatment with sulfuric acid produces the 4-hydroxyderivative XXXII. Protection of the alcohol functionality, for exampleas the TBS ether, followed by ester manipulation as described above andsubsequent alcohol deprotection, produces XXXIII. Treatment of XXXIIIwith a suitable base such as carbonate leads to ring closure to affordcompounds XXXIV. Alternatively, compounds XXXIII where X=OH can beclosed to XXXIV via a Mitsunobu reaction by treatment withdiethylazodicarboxylate and triphenylphosphine.

In scheme VI is shown how to make additional bicyclic systems in whichthe A-B residue is substituted on a carbon atom and the ring issubstituted with an R³ group. Ester XXVIII can be converted understandard conditions to the N-methoxy-N-methyl amide XXXV. Addition of anappropriate Grignard reagent R³MgBr produces a ketone, which uponN-deprotection and heating in acidic conditions leads to the substitutedpyridones XXXVI. Hydride reduction, with REDAL for example, will producethe piperidone XXXVII. Alternatively, diisobutylaluminum hydridereduction of the N-methoxy-N-methyl amide gives an aldehyde which willadd a suitable Grignard reagent R³MgBr to afford XXXVIII. Conversion ofthe alcohol to a leaving group, for example by making the mesylate withmethanesulfonyl chloride and a trialkylamine base, followed byN-deprotection leads to ring closure to piperidones XXXVII. The alcoholXXXVIII can also be prepared from enamine XXII from Scheme III byhydrolysis to the corresponding aldehyde followed by addition of theappropriate Grignard reagent R MgBr.

Preparation of a bicyclic system containing a seven-membered ring inwhich the A-B residue is attached to a carbon atom is described inScheme VII. N-protection of aminoketone XVII, where N-PG representspreferably an N-protected nitrogen wherein both N—H groups are masked,such as by conversion to an azide group, is followed by formation of aketone enolate, with a base such as lithium diisopropylamide, andreaction with a bromoacetate to afford XXXIX. N-deprotection followed byheating of the resulting amino ester affords XL. Alternatively, theester can be converted by straightforward means to a more reactivespecies prior to ring closure, such as a mixed anhydride or acidchloride. Treatment of XVII with bromoacetyl bromide and a base such astriethylamine gives the acylamine XLI that can be cyclized by formationof the ketone enolate with a base such as lithium diisopropylamide.

Additional seven-membered ring-containing bicyclic systems can beprepared as shown in Scheme VIII. The hydrazidoyl halide II, prepared asshown in Scheme I, can be cyclized with a cyanopyruvate in the presenceof a base such as alkoxide to afford 4-cyanopyrazole XLII. Esterdeprotection and coupling with H₂N-A-B as described in previous schemesyields cyanoamide XLIII. Reduction of the nitrile can be accomplished byvarious methods, such as by catalytic hydrogenation or by reduction withsodium borohydride in the presence of cobalt chloride. Cyclization ofthe resulting aminoamide using carbonyl diimidazole or other phosgeneequivalent as described previously affords compounds XLIV. For thecorresponding compound wherein the A-B residue is attached to carbon,the ester XLII can be converted to the N-methoxy-N-methyl amide asdescribed previously. Treatment of this amide with the enolate derivedfrom RO₂CH₂A-B yields the ketone XLV. Catalytic hydrogenation of thenitrile affords an amine that upon heating undergoes cyclization toafford XLVI. The oxygen containing analog corresponding to XLIV isobtained from ester VI, prepared as described in Scheme I. The group R′represents preferably a 2-furyl residue as a masked carboxylic acid.Reduction of the ester group of VI with a hydride reducing agent such asdiisobutylaluminum hydride is followed by protection of the resultingprimary alcohol, such as by a TBS ether. When R′ is 2-furyl, thecarboxylic acid can be unmasked by oxidation by a variety of reagents,including ozone, potassium permanganate, and sodium periodate in thepresence of ruthenium trichloride. Coupling with a suitable with H₂N-A-Bas described in previous schemes yields the amide XLVII. Deprotection ofthe alcohol affords a hydroxy amide, which can be cyclized usingcarbonyl diimidazole as described previously to afford compounds XLVIII.

Bicyclic compounds of Formula I containing a carbon atom at the pyrazole4-position are prepared by a [3+2] cycloaddition strategy as shown inScheme IX (for a review of [3+2] cycloadditions, see 1,3-DipolarCycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984).

Treatment of unsaturated lactone XLIX, which is readily available bystandard procedures known to those skilled in the art, with an aluminumreagent prepared from an appropriate amine H₂N-A-B and trimethylaluminumaffords the ring-opened amide L. Conversion of the primary alcohol understandard conditions to a suitable leaving group, such as a bromide ormesylate, and subjection to basic conditions affords the requiredunsaturated lactam LI. Treatment of hydrazidoyl halide II, prepared asshown in Scheme I where X=Cl or Br, with triethylamine generates a1,3-dipolar intermediate LII, which can undergo a [3+2] cycloadditionwith the olefin LI to produce the bicyclic pyrazolidine LIII as thepredominant regioisomer. Mild oxidation with reagents such as chloranilor nickel peroxide will produce the pyrazolopiperidones LIV. Furtheroxidation, such as with DDQ, can produce the unsaturated derivatives LV.These steps can be reversed such that initial complete oxidation to LVcan be followed by reduction, such as by catalytic hydrogenation, toproduce LIV. The ketone derivatives can be prepared by condensation ofan appropriate amine H₂N-A-B with the cyclic anhydride LVI to give LVII.Alternatively, a saturated derivative of LVI can be condensed with anappropriate amine H₂N-A-B followed by oxidation to the unsaturatedderivative LVII, such as by treatment with LDA/PhSeSePh and subsequentoxidative selenoxide elimination. The olefin LVII undergoes similar[3+2] cycloaddition to give a pyrazolidine intermediate that is readilyoxidized to the pyrazolopiperidinedione derivatives LVIII by a varietyof oxidizing agents.

An alternative preparation of compound LIV is also described. A standardalkylation/acylation sequence on the amine H₂N-A-B affords amide esterLIX, which contains a protected ketone functionality. A variety ofreaction conditions can be employed for these transformations, which areknown to those skilled in the art. Deprotection of the ketone followedby Dieckmann condensation under basic conditions affords the cyclicdiketoamides LX. Condensation of LX with an appropriate hydrazine isreadily accomplished by heating in a solvent such as acetic acid orethanol to afford the previously described LIV.

Pyrazolopiperidone compounds LXVI (where n=1) wherein the pyrazole4-substituent R^(1a) is a trifluoromethyl group can be prepared via themethod outlined in Scheme X. Coupling of the acid LXI with aminesH₂N-A-B can be accomplished under a variety of conditions, such as viathe acid chloride, giving amide LXII. A straightforward sequenceinvolving cleavage of the tetrahydrofuran ring and intramolecularcyclization on the amide nitrogen affords the ketolactam LXIII. Thiscompound can also be prepared from the lactam LXIV by introduction ofsulfur substituents and subsequent oxidation to the ketolactam LXIII.Formation of the morpholine or related enamine followed by reaction withtrifluoroacetic anhydride leads to the trifluoroacetylated intermediateLXV. Alternatively, dichlorination of lactam LXIV with PCl₅ or analogousreagents, heating with excess morpholine or related amine, and reactingthe enamine derived in this way with trifluoroacetic anhydride alsoyields the trifluoroacetylated intermediate LXV. This compound can bereadily condensed with an appropriate hydrazine to afford thepyrazolopiperidone compounds LXVI. Analogous chemistry can be utilizedto afford [5,7]-fused ring systems (where n=2).

Unsaturated analogs of the above compounds can be prepared as shown inthe bottom of Scheme X. Bromination of LXVII, prepared as described inScheme IX and the top of Scheme X, affords bromo analog LXVIII.Elimination of HBr by treatment with any of a variety of bases, such asDBU, will afford the unsaturated bicylic analogs LXIX. Additionalanalogs can be prepared by displacement of the bromide LXVIII by any ofa wide variety of nitrogen-, oxygen- and sulfur-based nucleophiles.

Additional [5,7]-fused bicyclic systems which contain an additionalheteroatom in the seven-membered ring can be prepared as shown in SchemeXI. Compounds LXXI where X is O or S can be prepared from commerciallyavailable tetrahydro-4H-pyran-4-one and tetrahydrothiopyran-4-one.Photoinduced Schmidt rearrangement of (triisopropylsilyl) azidohydrin(Evans, P. A. and Modi, D. P. J. Org. Chem. 1995, 60, 6662-6663), whichis formed from tetrahydro-4H-pyran-4-one and tetrahydrothiopyran-4-one,provides tetrahydro-1,4-oxazepin-5(2H)-one andtetrahydro-1,4-thiazepin-5(2H)-one. Compounds LXXI where X is NH or NRcan be prepared by Schmidt rearrangement of 4-piperidone monohydratehydrochloride or protected 4-piperidone (Groves, J. T. and Chambers, R.R. Jr. J. Am. Chem. Soc. 1984, 106, 630-638). Ullmann coupling of thelactam with I(Br)-A-B provides the lactam LXXII with an A-B residue.Dichloronation with phosphorus pentachloride or related reagent affordsa dichlorinated intermediate which can react with morpholine to give theenamine LXXIII. Reaction of LXXIII with DMAP and an appropriate acidchloride or acid anhydride provides the acylenamine intermediate LXXIVwhich can be condensed with an appropriate hydrazine in acetic acid toafford the [5,7]-fused bicyclic compounds LXXV.

Bicyclic compounds of Formula I which contain a carbon atom at thepyrazole 4-position and wherein the A-B residue is attached to a carbonatom are also prepared by a [3+2] cycloaddition strategy as shown inScheme XII. Unsaturated cyclic ketones LXXVI are readily available bystandard synthetic methods known to those skilled in the art. The [3+2]cycloaddition with the 1,3-dipole generated from II as describedpreviously gives a pyrazolidine intermediate that can be readilyoxidized to the pyrazolocyclohexanone LXXVII. Introduction of a doublebond, such as by treating with LDA and PhSeSePh followed by oxidativeselenoxide elimination, gives the unsaturated derivative LXXVIII.Incorporation of a residue such as a protected alcohol into theunsaturated ketone, represented by LXXIX, leads to pyrazolocyclohexanoneLXXX following [3+2] cycloaddition and subsequent oxidation.Deprotection of the alcohol and oxidation by a variety of reagentsaffords the pyrazolocyclohexanedione LXXXI.

Additional bicyclic compounds of Formula I containing a carbon atom atthe pyrazole 4-position are described in Scheme XIII. Condensation ofhydrazidoyl halide II with a diketoester in the presence of a base suchas alkoxide affords pyrazoles LXXXII. Heating this ketoester in thepresence of readily available hydrazines A-B-NHNH₂ affords thepyrazolopyridazinones LXXXIII. For preparation of pyrazolopyridazinoneswhere R³ is hydrogen, the hydrazidoyl halide II can be cyclized with afuryl ketoester in the presence of alkoxide base to afford LXXXIV.Standard functional group manipulations, involving ester reduction andprotection, furyl oxidation and esterification leads to LXXXV, althoughnot necessarily in that order. Those skilled in the art will be able todetermine a proper order and appropriate reagents for achieving thesetransformations. Alcohol deprotection and oxidation, such as bymanganese dioxide, affords an aldehyde ester which readily producesLXXXVI upon heating in the presence of a hydrazine A-B-NHNH₂.Appropriate functional group manipulation of LXXXIV, of which manymethods are available, can also afford ester acids LXXXVII. Activationof the carboxylic acid, such as by formation of the acid chloride withoxalyl chloride, followed by heating in the presence of a hydrazineA-B-NHNH₂ affords the pyrazolopyridazinedione LXXXVIII.

The preparation of the compounds of Formula I where the five-memberedring is triazole is accomplished using azide intermediates. Azidesreadily undergo [3+2] cycloaddition reactions with a variety of olefinsand alkynes, and the application of this reaction to the synthesis ofthe triazole-fused bicyclic compounds of Formula I is shown in SchemeXIV. As described for the pyrazole-fused compounds previously, the4-amino-1,2,3-triazole-5-carboxylate XCII is a particularly usefulintermediate for the preparation of many of the triazole-fused bicyclicsystems. The required azides LXXXIX are readily available. Aliphaticazides are easily prepared from the corresponding bromide bydisplacement with sodium azide in solvents such as dimethylformamide anddimethyl sulfoxide. Where “G-(CH₂),-” represents an aryl azide (G isaryl, s=0), the azides are readily available from the correspondinganiline by diazotization with NaNO₂ in acidic medium followed bydisplacement of the diazonium ion with sodium azide. The [3+2]cycloaddition of azides LXXXIX with nitroolefins XC (R′=Me, 2-furyl)affords the triazoles XCI as the major product, in which initialcyclization to a triazoline intermediate is followed by autooxidation tothe triazole products (Cailleux, P.; et. al. Bull. Soc. Chim. Belg.1996, 105, 45). These reactions can be performed in refluxing benzene orsimilar solvents at similar temperatures. Conversion of XCI to the4-amino-1,2,3-triazole-5-carboxylate XCII is straightforward. When R′ ismethyl, oxidation of the methyl group with an oxidant such as KlMnO₄gives the carboxylic acid which can be esterified to an appropriateester. Reduction of the nitro group by any of a variety of reducingagents, preferably SnCl₂ or catalytic hydrogenation, gives XCII. When R′is 2-furyl, the carboxylic acid can be unmasked by a variety ofoxidizing agents, including ozone, KMnO₄ and sodium periodate/rutheniumtrichloride, to give the carboxylic acid which can be esterified andreduced as described above to afford XCII. The4-hydroxy-1,2,3-triazole-5-carboxylates can be obtained via thediazonium ion of XCII as described for the pyrazole series to affordXCIV.

The reaction of azides LXXXIX with active methylene compounds is alsoillustrated in Scheme XIV. Treating LXXIX with cyano- or nitropyruvatesin the presence of a base such as alkoxide affords triazoles XCIII. Thetriazole-4-carboxylate derivatives can be prepared by treating LXXXIXwith a furyl ketoester in the presence of alkoxide base to afford XCV.These reactions are analogous to those described in Scheme I for thepyrazole derivatives. The triazole-containing bicyclic systems having acarbon atom at the 4-position of the triazole can be prepared by [3+2]cycloaddition of an appropriate azide LXXXIX with an unsaturated lactamLI or an unsaturated cyclic ketone LXXVI. These cycloadditions areperformed by heating in an appropriate solvent, such as benzene ortoluene. The resulting triazoline intermediates are readily oxidized tothe fused triazoles using chloroanil, nickel peroxide or other mildoxidant to give XCVI and XCVII, respectively. The triazole intermediatesXCI, XCII, XCIII, XCIV, XCV, XCVI and XCVII can be transformed into thefinal triazole-containing bicyclic compounds described by Formula Ifollowing the procedures described for the corresponding pyrazolederivatives in Schemes II-XI. The nitro group present in XCI and XCIIIcan correspond to the “N-PG” residue described in Schemes II-VIII, oralternatively, the nitro group can be reduced at an appropriate time andfurther protected as a suitable carbamate derivative or as an azidogroup.

The preparation of the compounds of Formula I where the five-memberedring is isoxazole is accomplished as shown in Scheme XV. Thehydroximinoyl chloride XCIX is a useful intermediate for the preparationof isoxazole-fused compounds. This intermediate is readily availablefrom appropriate aldehydes XCVIII by oxime formation with hydroxylaminefollowed by chlorination with N-chlorosuccinimide. Treatment of XCIXwith a cyanoacetate in the presence of a base such as carbonate resultsin cyclization to give a 5-aminoisoxazole-4-carboxylate C. The aminoresidue of C can be readily converted into the corresponding hydroxy orcyano derivatives CI and CII, respectively, via the diazonium ion, asdescribed earlier for the pyrazole and triazole compounds.

The isoxazole-5-carboxylates are available from cyclization of XCIX witha furan ketoester to give CIII. Oxidation of the furan to a carboxylicacid residue is accomplished by a variety of oxidizing agents asdescribed earlier.

The hydroxyiminoyl chloride XCIX can also be treated with a base such astriethylamine to generate a nitrile oxide intermediate, which canundergo [3+2] cycloaddition reactions with appropriate olefins oralkynes. This is a convenient method by which to prepare bicycliccompounds containing a carbon atom at the 5-position of the isoxazolering. For example, cycloaddition with the unsaturated lactam LI leads toformation of a fused isoxazoline intermediate which is readily oxidizedwith reagents such as nickel peroxide, chloranil or DDQ to afford CIV.Cycloaddition with unsaturated cyclic ketone and oxidation under thesame conditions affords the ketone analog Cv. The isoxazole-fusedintermediates C, CI, CII, CIII, CIV and CV can be transformed into thefinal isoxazole-containing bicyclic compounds described by Formula Ifollowing the procedures described for the corresponding pyrazolederivatives in Schemes II-XI.

The preparation of the compounds of Formula I where the five-memberedring is isothiazole is accomplished as shown in Scheme XVI. One methodfor preparing the 5-aminoisothiazole-4-carboxylate intermediate CVIIIproceeds from readily available acid chloride CVI. Condensation of CVIwith a cyanoacetate in the presence of a base such as a magnesiumalkoxide followed by treatment with ammonia in an alcoholic solventgives an aminonitrile CVII. Treatment with hydrogen sulfide in thepresence of a base such as triethylamine affords a thioamide that canundergo an oxidative cyclization to CVIII upon treatment with hydrogenperoxide or bromine. As described in previous schemes, the amino residuecan easily be converted into the corresponding hydroxyl or cyanoderivatives CIX or CX, respectively.

Another useful intermediate for the preparation of isothiazole compoundsof the present invention is the nitrile sulfide CXIII. This intermediatecan be generated conveniently from heterocycle CXII, which itself can beprepared from amides CXI either by treating with chlorocarbonylsulfenylchloride or by treating with trichlorbmethanesulfenyl chloride followedby aqueous sodium hydroxide. Thermolysis of heterocycle CXII affords thenitrile sulfide CXIII, which can undergo many of the same reactions asthe corresponding nitrile oxide intermediates. For example, [3+2]cycloaddition of CXIII with olefins LI and LXXVI can afford, aftersubsequent mild oxidation as described previously, the isothiazole-fusedcompounds CXIV and CXV, respectively. Isothiazole intermediates CVIII,CIX, CX, CXIV and CXV can be transformed into the finalisothiazole-containing bicyclic compounds described by Formula Ifollowing the procedures described for the corresponding pyrazolederivatives in Schemes II-XI.

Formula I also describes pyrazole-fused bicyclic compounds in which the“G-(CH₂),-” group resides on a carbon atom of the pyrazole ring. Thesecompounds can be prepared as shown in Scheme XVII. Condensation of acidchlorides CVI with cyanoacetates in the presence of a base such asmagnesium methoxide affords an enol derivative that is converted to theenol ether CXVI (X═OMe) with diazomethane or to the chloro derivativeCXVI (X=Cl) with POCl₃. Heating with hydrazine (R′=H) or a substitutedhydrazine affords 5-amino-4-carboxylate CXVII. The amino residue ofCXVII can be converted to the hydroxyl or cyano derivative CXVIII orCXIX, respectively via the diazonium ion as described previously.

The 5-carboxylate derivatives can be prepared by condensing asubstituted hydrazine with a hemiacetal or related derivativerepresented by CXX. Chlorination or bromination with NCS or NBS,respectively, affords the hydrazidoyl halides CXXI. Reaction of CXXIwith the anion of a furyl ketoester affords the 5-carboxylate CXXII, thefuran residue of which can be oxidized to a carboxylic acid residue bymethods described previously.

The hydrazidoyl halides CXXI can also participate in [3+2]cycloadditions as described previously to afford, after oxidation of theintermediate pyrazolines, the pyrazole-fused compounds CXXIII and CXXIV.The intermediates CXVII, CXVIII, CXIX, CXXII, CXXIII and CXXIV can betransformed into the final C-linked pyrazole-containing bicycliccompounds described by Formula I following the procedures described forthe corresponding N-linked pyrazole derivatives in Schemes II-XI.

Bicyclic compounds of the present invention in which the five memberedring is pyrrole and the G-containing group is attached to a carbon atomcan be prepared as shown in Scheme XVIII. For compounds of this typewherein a nitrogen atom is required at the pyrrolo 2-position, the2-aminopyrrole CXXVI is a useful intermediate. This compound can beprepared by condensation of readily obtained aminocarbonyl compoundsCXXV with an appropriate cyanoacetate. This condensation can be carriedout under basic conditions or by heating with azeotropic removal ofwater. The 2-aminopyrroles CXXVI can be diazotized and subsequentlyconverted into the 2-cyano- and 2-hydroxypyrroles CXXVII, which aresuitable intermediates for a variety of the bicyclic compounds of thisinvention. Pyrrole 2,3-dicarboxylates can also be prepared fromaminocarbonyl compounds CXXV. Michael addition under basic conditionswith acetylenedicarboxylate esters is followed by in situ ring closureto afford the pyrrole 2,3-dicarboxylate diester. Selective hydrolysis ofone of the esters, typically the 2-ester, affords the pyrrole2-carboxylic acid CXXVIII. Curtius rearrangement of CXXVIII affordsanother route to the 2-aminopyrrole CXXVI. Also, the carboxylic acid canbe reduced to the alcohol CXXIX using borane or by sodium borohydridereduction of the derived mixed anhydride. Following procedures describedin Schemes II-VIII and Scheme XIII, the intermediates CXXVI, CXXVII,CXXVIII and CXXIX can be converted to the final pyrrolo-fused bicycliccompounds of Formula I. Other procedures not described here are alsoknown to those skilled in the art and can be used to prepare thepyrrolo-fused bicyclic compounds of Formula I.

Bicyclic compounds of the present invention in which the five memberedring is furan and the G-containing group is attached to a carbon atomcan be prepared as shown in Scheme XIX. For compounds of this typewherein a nitrogen atom is required at the furyl 2-position, the2-aminofuran CXXXI is a useful intermediate. These compounds can beprepared analogously to the pyrrole analogs described in Scheme XVIII.Thus, condensation of readily obtained hydroxycarbonyl compounds CXXXwith an appropriate cyanoacetate affords the 2-aminofurans CXXXI. Thiscondensation can be carried out under basic conditions or by heatingwith azeotropic removal of water. The 2-aminofurans CXXXI can bediazotized and subsequently converted into the 2-cyano- and2-hydroxyfurans CXXXII, which are suitable intermediates for a varietyof the bicyclic compounds of this invention. Furan 2,3-dicarboxylatescan also be prepared from hydroxycarbonyl compounds CXXX, analogously tothe pyrrole analogs described in Scheme XVIII. Michael addition of CXXXunder basic conditions with acetylenedicarboxylate esters is followed byin situ ring closure to afford the furan 2,3-dicarboxylate diester.Selective hydrolysis of one of the esters, typically the 2-ester,affords the furan 2-carboxylic acid CXXXIII. Curtius rearrangement ofCXXXIII affords another route to the 2-aminofurans CXXXI. Also, thecarboxylic acid can be reduced to the alcohol CXXXIV using borane or bysodium borohydride reduction of the derived mixed anhydride. Followingprocedures described in Schemes II-VIII and Scheme XIII, theintermediates CXXXI, CXXXII, CXXIII and CXXXIV can be converted to thefinal furan-fused bicyclic compounds of Formula I. Other procedures notdescribed here are also known to those skilled in the art and can beused to prepare the furan-fused bicyclic compounds of Formula I.

Bicyclic compounds of the present invention in which the five memberedring is thiophene and the G-containing group is attached to a carbonatom can be prepared as shown in Scheme XX. For compounds of this typewherein a nitrogen atom is required at the thiophene 2-position, the2-aminothiophene CXXXVI is a useful intermediate. These compounds can beprepared analogously to the pyrrole analogs described in Scheme XVIII.Thus, condensation of readily obtained mercaptocarbonyl compounds CXXXVwith an appropriate cyanoacetate affords the 2-aminothiophenes CXXXVI.This condensation can be carried out under basic conditions or byheating with azeotropic removal of water. Alternatively, condensation ofthe cyanoacetate with ketone CXXXVIII affords olefin CXXXIX. In asubsequent step, CXXXIX can be converted into 2-aminothiophenes CXXXVIby treatment with S₈ and a base such as triethylamine. The2-aminothiophenes CXXXVI can be diazotized and subsequently convertedinto the 2-cyano- and 2-hydroxythiophenes CXXXVII, which are suitableintermediates for a variety of the bicyclic compounds of this invention.Thiophene 2,3-dicarboxylates can be prepared from alkali-metalacetylenethiolates CXL. These compounds react withacetylenedicarboxylate esters in a [3+2] cycloaddition to affordthiophene 2,3-dicarboxylate diesters. Selective hydrolysis of one of theesters, typically the 2-ester, affords the thiophene 2-carboxylic acidCXLI. Curtius rearrangement of CXLI affords another route to the2-aminothiophenes CXXXVI. Also, the carboxylic acid can be reduced tothe alcohols CXLII using borane or by sodium borohydride reduction ofthe derived mixed anhydride. Following procedures described in SchemesII-VIII and Scheme XIII, the intermediates CXXXVI, CXXXVII, CXLI andCXLII can be converted to the final thiophene-fused bicyclic compoundsof Formula I. Other procedures not described here are also known tothose skilled in the art and can be used to prepare the thiophene-fusedbicyclic compounds of Formula I.

Bicyclic compounds of the present invention in which the five memberedring is imidazole and the G-containing group is attached to a nitrogenatom can be prepared as shown in Scheme XXI. These compounds CXLIIIthrough CLXIV, where the R group may be alkyl, aryl or a protectinggroup PG, are available either from commercial sources or through knownprior art and can be represented generically by CLXV. Suitableprotection of the imidazole nitrogen affords compounds of the typeCLXVI, which are further elaborated via a cupric mediated coupling ofappropriate A-B containing boronic acid to yield CLXVII. Subsequentremoval of the imidazole-protecting group PG affords compounds such asCLXVIII. The introduction of a substituent G is accomplished as beforeby the coupling of a G-containing boronic acid in a manner such that theG-group is transferred to the imidazole nitrogen as depicted by CLVIX.

The A-B moieties can be prepared by methods known to those of skill inthe art. The following publications, the contents of which areincorporated herein by reference, describe and exemplify means ofpreparing A-B moieties: WO97/23212, WO97/30971, WO97/38984, WO98/06694,WO98/01428, WO98/28269, and WO98/28282.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 11-[4-methoxyphenyl]-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4-dihydropyrazolo-[4,3-d]-pyrimidine-5,7-dione.

Part A. □, □-Dicyano-4-methoxyphenyl hydrazine imine

Anisidine (18.84 g, 152.99 mmol) was dissolved in 225 mL of waterfollowed by the addition of 32.7 mL (392.4 mmol) of concentrated HCl andthen the mixture was cooled in an ice bath. NaNO₂ (13.72 g, 198.89 mmol)was dissolved in 45 mL of water and added in several portions. Thesolution was stirred for 10 minutes and poured into a flask containing asolution of 10.10 g (152.99 mmol) of malononitrile and sodium acetate(27.61 g, 336.59 mmol) in 36 mL of methanol and 75 mL of water. A heavyyellow precipitate immediately formed (29.9 g, 97%) and was isolated asthe title compound by suction filtration. LRMS (NH₃—CI): 218.2 (M+NH₄)⁺.

Part B.Methyl(1-[4-Methoxyphenyl]-3-cyano-4-amino)pyrazole-5-carboxylate.

□, □-Dicyano-4-methoxyphenyl hydrazine imine (20.00 g, 99.92 mmol),methyl bromoacetate (16.81 g, 109.90 mmol), 4-N,N-dimethyl pyridine(1.22 g, 9.99 mmol) and potassium carbonate (34.52 g, 249.79 mmol) weredissolved in N,N-dimethyl formamide and heated to 100° C. for severalhours. The solution was diluted with ethyl acetate and washed 4 timeswith brine. The organics were dried over MgSO₄, filtered through a padof silica gel and the volatiles were removed. The title compound waspurified by dissolving in hot diethyl ether and collecting the solids(9.18 g, 34%) that formed upon cooling by filtration. LRMS (ES⁺): 273.2(M+H)⁺.

Part C.Methyl(1-[4-Methoxyphenyl]-3-cyano-4-azido)pyrazole-5-carboxylate.

Methyl(1-[4-Methoxyphenyl]-3-cyano-4-amino)pyrazole-5-carboxylate (3.36g, 12.34 mmol) was dissolved in TFA and cooled to 0° C. followed by theaddition of NaNO₂ (0.94 g, 13.57 mmol) and then the reaction was stirredat that temperature for 45 min. NaN₃ (0.80 g, 12.34 mmol) was dissolvedin a minimal amount of water and added in portions to the TFA solution.The solution was allowed to stir at 0° C. for 45 min and added slowly toa saturated water solution of NaHCO₃. The solution was diluted withethyl acetate and washed twice with brine. The organics were dried overMgSO₄, filtered through a plug of silica gel and the volatiles wereremoved to give the title compound as a tan solid (1.0 g, 57%). LRMS(NH₃—CI): 316.3 (M+NH₄)⁺.

Part D.1-[4-methoxyphenyl]-3-cyano-4-azido-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl[aminocarbonyl]pyrazole.

[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]amine hydrochloride (1.00g, 3.31 mmol) was dissolved in anhydrous methylene chloride followed bythe addition of trimethylaluminum (9.94 mL. 19.88 mmol) as 2.0 Msolution in toluene. The solution was stirred at ambient temperatureuntil gas evolution ceased.Methyl(1-[4-Methoxyphenyl]-3-cyano-4-azido)pyrazole-5-carboxylate (0.988g, 3.31 mmol) was added and the solution stirred overnight at roomtemperature and refluxed for an additional 2 hrs. The solution wasallowed to cool to room temperature and the solution slowly quenchedwith a saturated solution of ammonium chloride. The reaction was dilutedwith ethyl acetate and washed twice with a 5% solution of citric acid.The organics were dried over MgSO₄ and filtered through a plug of silicagel. The title compound was purified by column chromatography elutingwith 1:1 hexane/ethyl acetate (0.09 g, 5%). LRMS (ES−): 530.1 (M−H)⁻.

Part E.1-[4-methoxyphenyl]-3-cyano-4-amino-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole.

1-[4-methoxyphenyl]-3-cyano-4-azido-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole(0.09 g, 0.169 mmol) was dissolved in methanol followed by the additionof SnCl₂2 H₂O (0.321 g, 1.69 mmol) and the solution refluxed for 1 hr.The volatile were removed under reduced pressure and the residue stirredin TFA, filtered through a pad of Celite® and the residue purified bypreparative HPLC chromatography to yield the title compound as a whitesolid (30 mg 19%). LRMS (ES⁺): 506.3 (M+H)³¹.

Part F.1-[4-methoxyphenyl]-3-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4-dihydropyrazolo-[4,3-d]-pyrimidine-5,7-dione.

1-[4-methoxyphenyl]-3-cyano-4-amino-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole(0.02 g, 0.032 mmol) was dissolved in THF followed by the addition ofcarbonyl diimidazole (0.010 g, 0.064 mmol) and the solution was stirredat room temperature for 48 hrs. and then at reflux for 0.5 hrs. Thevolatiles were removed under reduced pressure and the product purifiedby preparative HPLC (C18 reverse phase column, elution with a H₂O/CH₃CNgradient with 0.5% TFA) and lyophilized to afford the title compound ofExample 1 as a white powder (1.9 mg, 11%). LRMS (ES−): 530.2 (M−H)⁻

Example 21-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

Part A. (1-[4-Methoxyphenyl]-3-cyano-4-azido)pyrazole-5-carboxylic acid.

Methyl(1-[4-Methoxyphenyl]-3-cyano-4-azido)pyrazole-5-carboxylate (5.9g, 19.78 mmol) was dissolved in a 1:1:1 mixture of MeOH/H₂O/THF followedby the addition of NaOH (1.58 g, 39.56 mmol) and the reaction wasallowed to stir at room temperature until all of the starting materialwas consumed by TLC. The solution was acidified with 10% HCl and theproduct was extracted with ethyl acetate. The organic layer was washedtwice with brine and the solvent was dried over MgSO₄, filtered and thevolatiles were removed under reduced pressure to yield the titlecompound as a tan solid (4.00, 71%). LRMS (ES−): 539.0 (M−H—CO₂)³¹ .

Part B. 1-[4-methoxyphenyl]-3-cyano-4-azido-5-[2-fluoro-4-bromophenyl)aminocarbonyl]pyrazole.

1-[4-methoxyphenyl]-3-cyano-4-azidopyrazole-5-carboxylic acid (4.00 g,14.07 mmol) was dissolved in CH₂Cl₂ followed by the addition of oxalylchloride (1.84 mL, 21.11 mmol) and 1 drop of DMF. The mixture wasallowed to stir at room temperature for 2 hrs. The volatiles wereremoved under reduced pressure and the residue dried under high vacuumfor 1 hr. The residue was dissolved in CH₂Cl₂ followed by the additionof DMAP (3.44 g, 28.15 mmol) and 2-fluoro-4-bromo-aniline (2.67 g, 14.07mmol) and the solution stirred overnight at room temperature. Thevolatiles were removed under vacuum and the product purified bytrituration of the residue with ether/hexanes to afford the titlecompound (1.50 g, 23%). LRMS (ES−): 454.0 (M−H)⁻.

Part C.1-[4-methoxyphenyl]-3-(methoxycarbonyl)-4-amino-5-[2-fluoro-4-bromophenyl)aminocarbonyl]pyrazole.

1-[4-methoxyphenyl]-3-cyano-4-azido-5-[2-fluoro-4-bromophenyl)aminocarbonyl]pyrazole(1.50 g, 3.28 mmol) was dissolved in MeOH followed by the addition oftin (II) chloride dihydrate (6.23, 32.88 mmol) and the solution refluxedfor 2 hrs. The solution was dissolved in EtOAc and basified by theaddition of 10% NaOH solution. The organics were washed twice with brineand dried over MgSO₄ filtered through a pad of silica gel and driedunder vacuum to give the title compound (0.55 g, 39%). LRMS (ES⁺): 463.1(M+H)⁺.

Part D.1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2-fluoro-4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

1-[4-methoxyphenyl]-3-methoxycarbonyl-4-amino-5-[2-fluoro-4-bromophenyl)aminocarbonyl]pyrazole(0.55 g, 1.27 mmol) was dissolved in 25 mL of 96% formic acid andrefluxed for 3 hrs. The volatile were removed and the residue dissolvedin EtOAc and washed with a saturated solution of NaHCO₃. The organicswere dried over a solution of MgSO₄, filtered through a plug of silicagel and the volatiles were removed to yield the title compound as awhite solid (0.30 g, 50%). LRMS (ES⁺): 473.1 (M+H)⁺.

Part E.1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2-fluoro-4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.30 g, 0.633 mmol), TBAB (0.02 g, 0.06 mmol), aqueous Na₂CO₃ (2M, 0.7mL, 0.88 mmol), and 2-(N-tert-butyl)phenylsulfonamide boronic acid (0.22g, 0.88 mmol) were dissolved in 100 mL of benzene and degassed withnitrogen for 30 minutes. Following the purge,tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mol) was addedand the solution stirred overnight at reflux. The solution was dilutedwith EtOAc and washed twice with brine and the organics dried overMgSO₄, filtered and the volatiles were removed under reduced pressure.Purification by column chromatography, eluting with 1:1 hexane/EtOAc,afforded 0.20 g (52%) of a tert-butyl sulfonamide. This compound (0.20g, 0.33 mmol) was dissolved in 25 mL of TFA and refluxed for 1 hour. Thevolatiles were removed under reduced pressure and the product waspurified by reverse phase HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford the titlecompound of Example 2 as a white solid. LRMS (ES⁺): 550.2 (M+H)⁺.

Example 31-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

Part A. (1-[4-Methoxyphenyl]-3-cyano-4-azido)pyrazole-5-carboxylic acid.

Methyl(1-[4-Methoxyphenyl]-3-cyano-4-azido)pyrazole-5-carboxylate fromExample 1, Part C (14.0 gr, 46.94 mmol) was dissolved in a 1:1 solutionof THF/H₂O followed by the addition of lithium hydroxide monohydrate(5.90 g, 140.84 mmol) and the solution stirred at room temperature for 4hours. The solution was acidified with HCl, the organics were extractedwith EtOAc and washed with brine. The organic layer was dried overMgSO₄, filtered through a plug of silica gel and the volatiles removedunder reduced pressure to yield 8.72 g (65%) of the title compound as atan solid. LRMS (ES−): 283.1 (M−H)⁻.

Part B. 1-[4-methoxyphenyl]-3-cyano-4-azido-5-[(2-fluoro-4-bromophenyl)aminocarbonyl pyrazole.

To a solution of(1-[4-Methoxyphenyl]-3-cyano-4-azido)pyrazole-5-carboxylic acid (8.22 g,28.92 mmol) in CH₂Cl₂ was added oxallyl chloride (3.78 mL, 43.38 mmol)and 1 drop of DMF. The mixture was allowed to stir at room temperaturefor 2 hours. The volatiles were removed under reduced pressure and theresidue dried under high vacuum for 1 hour. The residue was dissolved inCH₂Cl₂ followed by the addition of DMAP (7.06 g, 57.84 mmol) and2-fluoro-4-bromoaniline (5.49 g, 28.92 mmol) and the solution stirredovernight at room temperature. The volatiles were removed under vacuumand the product was purified by trituration of the residue withhexane/ether to give 7.9 g (60%) of the title compound as a solid. LRMS(ES−): 454.0/456.0 (M−H)⁻.

Part C.1-[4-methoxyphenyl]-3-(aminocarbonyl)-4-azido-5-[(2-fluoro-4-bromophenyl)aminocarbonyl]pyrazole.

A solution of1-[4-methoxyphenyl]-3-cyano-4-azido-5-[(2-fluoro-4-bromophenyl)aminocarbonyl]pyrazole(1.00 g, 2.32 mmol) in a 1:1 mixture of MeOH:MeOAc was cooled in anice/water bath. Gaseous HCl was bubbled through the cooled solution for15 minutes and the solution was stirred, with warming to roomtemperature, overnight. The volatiles were removed under reducedpressure followed by the addition of 25 mL of MeOH and 20 mL of 1 M HCland the resulting solution was stirred at room temperature for 2 hours.The solution was diluted with EtOAc, washed with brine, the organicswere dried over MgSO₄, filtered through a pad of silica gel and thevolatiles were removed under reduced pressure to give 0.99 g (95%) ofthe title compound as a tan solid. LRMS (ES+): 458.1/460.1 (M+H)⁺.

Part D.1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2-fluoro-4-bromophenyl]-1,6-dihyropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-(aminocarbonyl)-4-azido-5-[(2-fluoro-4-bromophenyl)aminocarbonyl]pyrazole(0.99 g, 2.20 mmol) in methanol was added tin (II) chloride dihydrate(6.23, 32.88 mmol) and the solution refluxed for 2 hrs. The solution wasdissolved in EtOAc and basified by the addition of 10% NaOH solution.The organics were washed twice with brine and dried over MgSO₄ filteredthrough a pad of silica gel and dried under vacuum. The residue wasdissolved in 50 mL of 95% formic acid was stirred at reflux for 2 hours.The volatiles were removed under reduced pressure and the residue washeated in methanol and filtered to afford 0.69 g (68%) of the titlecompound as a solid. LRMS (ES⁺): 458.1/460.1 (M+H)⁺.

Part E.1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2-fluoro-4-bromophenyl]-1,6-dihyropyrazolo-[4,3-d]-pyrimidin-7-one(0.69 g, 1.50 mmol), TBAB (0.048 g, 0.15 mmol), aqueous Na₂CO₃ (2M, 3.0mL, 6.0 mmol) and 2-(tert-butylaminosulfonyl)phenylboronic acid (0.54 g,2.1 mmol) were dissolved in 100 mL of benzene and degassed with nitrogenfor 30 minutes. Following the purge,tetrakis(triphenylphosphine)palladium(0) (0.087 g, 0.075 mmol) was addedand the solution stirred overnight at reflux. The solution was dilutedwith EtOAc and washed twice with brine and the organics dried overMgSO₄, filtered and the volatiles removed under reduced pressure. Thetitle compound was purified by column chromatography eluting with 1:1hexane/EtOAc to afford 0.26 g (29%) of the title compound. LRMS (ES⁺):573.3 (M+H)⁺.

Part F.1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

A solution of1-(4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.26 g, 0.44 mmol) in 25 mL of TFA was refluxed for 1 hour. Thevolatiles were removed under reduced pressure and the product purifiedby reverse phase HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford the titlecompound of Example 3 as a white solid. LRMS (ES⁺): 535.2 (M+H)⁺.

Example 41-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

Part A. □-Cyano-.□-(methoxycarbonyl)-4-methoxyphenyl hydrazine imine

Anisidine (55.0 g, 446.57 mmol) was dissolved in 675 mL of waterfollowed by the addition of 98.1 mL (1.1 mol) of concentrated HCl andthe mixture cooled in an ice bath. NaNO₂ (40.05 g, 580.54 mmol) wasdissolved in 100 mL of water and added in several portions. The solutionwas stirred for 10 minutes and poured into a flask containing a solutionof 44.25 g (446.57 mmol) of methyl cyanoacetate and sodium acetatetrihydrate (133.69 g, 446.57 mmol) in a solution of methanol and water(108:225 mL). A heavy yellow precipitate immediately formed and wasisolated by suction filtration and dried on a lyophilizer to give 82.0 g(79%) of the title compound as a yellow solid. LRMS (ES⁺): 232.1 (M−H)⁻.

Part B.tert-Butyl(1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-4-amino)pyrazole-5-carboxylate.

□-Cyano-□-(methoxycarbonyl)-4-methoxyphenyl hydrazine imine (105.7 g,455.2 mmol), tert-butyl bromoacetate (106.5 g, 546.2 mmol), andpotassium carbonate (157.3 g, 1.13 mol) were dissolved inN,N-dimethylformamide and heated to 100° C. for several hours. Thesolution was diluted with ethyl acetate and washed 4 times with brine.The organics were dried over MgSO₄, filtered through a pad of silica geland the volatiles removed. The title compound was obtained as a darkviscous liquid and used without any further purification (136.7 g, 86%).LRMS (NH₃—CI): 348.3 (M+H)⁺.

Part C.(1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-4-azido)pyrazole-5-carboxylicacid.

To a solution of tert-butyl(1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-4-amino)pyrazole-5-carboxylate(16.89 g, 48.62 mmol) in 100 mL of TFA at 0° C. was added NaNO₂ (4.02 g,58.34 mmol) and the mixture was stirred for 45 min. NaN₃ (3.79 g, 58.34mmol) was dissolved in a minimal amount of water and added in portionsto the TFA solution. The solution was allowed to sir at 0° C. for 45min. and added slowly to a saturated aqueous solution of NaHCO₃. Thesolution was diluted with ethyl acetate and washed three times withwater. The aqueous layer was acidified with 10% aqueous HCl andextracted with EtOAc. The organics were dried over MgSO₄, filteredthrough a plug of silica gel. The product was obtained by flushing thesilica gel with 1:1 EtOAc:MeOH. The volatiles were removed under reducedpressure to give 3.0 g (32%) of the title compound as a tan solid. LRMS(ES−): 316.1 (M−H)³¹

Part D.1-[4-methoxyphenyl]-3-(methoxycarbonyl)-4-azido-5-[4-bromophenylaminocarbonyl]pyrazole.

To a solution of(1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-4-azido)pyrazole-5-carboxylicacid (3.00 g, 9.45 mmol) in 20 mL of CH₂Cl₂ was added oxallyl chloride(1.24 mL, 14.18 mmol) and 1 drop of DMF. The mixture was allowed to stirat room temperature for 2 hours. The volatiles were removed underreduced pressure and the residue dried under high vacuum for 1 hour. Theresidue was dissolved in CH₂Cl₂ followed by the addition of DMAP (4.0 g,33.1 mmol) and 4-bromoaniline (1.62 g, 9.45 mmol) and the solutionstirred overnight at room temperature. The volatiles were removed undervacuum and the product purified by trituration of the residue withether/hexanes to afford the title compound (1.5 g, 33%). LRMS (ES−):454.0 (M−H)⁻

Part E.1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-(methoxycarbonyl)-4-azido-5-[4-bromophenylaminocarbonyl]pyrazole(1.5 g, 3.18 mmol) in isopropanol was added tin (II) chloride dihydrate(0.43 g, 2.28 mmol) and the solution was warmed for 5 minutes. Thesolution was filtered through a pad of silica gel and the silica rinsedwith EtOAc. The volatiles were removed under reduced pressure and theresidue was refluxed for 2 hours in 95% formic acid. The volatiles wereremoved under reduced pressure and the solid residue was washed withcold EtOAc and collected by suction filtration to afford 1.44 g (93%) ofthe title compound as a solid. LRMS (ES⁺): 455.1/457.1 (M+H)⁺

Part F.1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-14,3-d]-pyrimidin-7-one.

A solution of1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.60 g, 1.32 mmol), TBAB (0.04 g, 0.13 mmol), aqueous Na₂CO₃ (2M, 2.6mL, 5.28 mmol), and 2-(tert-butylaminosulfonyl)phenylboronic acid (0.47g, 1.84 mmol) in 100 mL of benzene was degassed with a stream ofnitrogen for 30 minutes. Following the purge,tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol) was addedand the solution was stirred overnight at reflux. The solution wasdiluted with EtOAc and washed twice with brine and the organics driedover MgSO₄, filtered and the volatiles removed under reduced pressure.The residue was purified by column chromatography (elution with 1:1hexane/EtOAc) to afford 0.2 g (52%) of a t-butylsulfonamide. A portionof this compound (0.08 g, 0.136 mmol) was dissolved in 30 mL of TFA andrefluxed for 1 hour. The volatiles were removed under reduced pressureand the product was purified by reverse phase HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford the title compound of Example 4 as a white solid. LRMS (ES⁺):532.2 (M+H)⁺.

Example 51-[4-methoxyphenyl]-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one-3-carboxylicacid.

To a solution of1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 4, Part F (150 mg, 0.28 mmol) in a 1:1 mixture of MeOH:H₂Owas added LiOH (120 mg, 2.82 mmol) and the reaction was followed by TLC.The solution was quenched by the addition of 10% HCl until acidic tolitmus and the product purified by reverse phase HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford the title compound of Example 5 as a white solid. LRMS (ES):516.1 (M−H)⁻

Example 61-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 4, Part F (1.00 gr, 1.70 mmol) in 20 mL of 1,4-dioxane wasadded 25 mL of aqueous (28%) ammonia and the reaction was stirred atroom temperature overnight. The solution was diluted with EtOAc andwashed with 100 mL of brine. The organics were dried over MgSO₄,filtered through a plug of silica gel and the volatiles removed underreduced pressure. The residue (0.08 g, 0.139 mmol) was dissolved in 30mL of TFA and refluxed for 1 hour. The volatiles were removed underreduced pressure and the product purified by reverse phase HPLC (C18reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA)and lyophilized to afford the title compound of Example 6 as a whitesolid. LRMS (ES⁺): 535.1 (M+H)⁺.

Example 71-[4-methoxyphenyl]-3-cyano-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 6, Part A (0.25 g, 0.436 mmol) in 50 mL of anhydrousbenzene was added phosphorous oxychloride (0.33 g, 2.18 mmol) and thereaction was allowed to reflux for 3 hours. The solution was quenchedwith H₂O and the product extracted with EtOAc, dried over MgSO₄,filtered through a plug of silica gel and the volatiles removed underreduced pressure. The residue was dissolved in 30 mL of TFA and refluxedfor 1 hour. The volatiles were removed under reduced pressure and theproduct purified by reverse phase HPLC (C18 reverse phase column,elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized toafford the title compound of Example 7 as a white solid. LRMS (ES⁺):499.2 (M+H)⁺.

Example 81-[4-methoxyphenyl]-3-(aminomethyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt.

To a solution of1-[4-methoxyphenyl]-3-cyano-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 7, Part A (0.50 g, 1.00 mmol) in 75 mL of absolute EtOHcontaining 1 mL of TFA was added 10% Pd/C (50 mg) and the reaction wasstirred overnight under a balloon of H₂ gas. The solution was filteredthrough a pad of Celite® and the volatiles were removed under reducedpressure and the product purified by reverse phase HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford the title compound of Example 8 as a white solid.LRMS (ES⁺): 503.3 (M+H)⁺.

Example 91-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

Part A. □-Cyano-.□-(ethoxycarbonyl)-4-methoxyphenyl hydrazine imine.

Anisidine (110 g, 0.89 mol) was dissolved in 1 L of water followed bythe addition of 196 mL (2.35 mol) of concentrated HCl and then themixture was cooled in an ice bath. NaNO₂ (67.8 g, 0.98 mol) wasdissolved in 250 mL of water and added in several portions. The solutionwas stirred for 15 minutes and then poured into a flask containing asolution of ethyl cyanoacetate (111 g, 0.98 mol) and sodium acetatetrihydrate (267 g, 1.96 mol) in 215 mL of methanol and 450 mL of waterat 0° C. A heavy yellow precipitate immediately formed. After 30 minutes187 g (84%) of the title compound was isolated by suction filtration andwas used without further purification.

Part B. 3-Ethyl-5-methyl(1-[4-Methoxyphenyl]-4-amino)pyrazole-3,5-dicarboxylate.

□-Cyano-.□-(ethoxycarbonyl)-4-methoxyphenyl hydrazine imine (81.8 g, 331mmol), methyl bromoacetate (55.7 g, 364 mmol) and potassium carbonate(114 g, 0.827 mmol) were dissolved in N,N-dimethyl formamide and heatedto 100° C. for several hours. The solution was diluted with ethylacetate and washed 4 times with brine. The organics were dried overMgSO₄, filtered through a pad of silica gel and the volatiles wereremoved. The title compound was purified by dissolving in hot diethylether and collecting the solids (24.3 g, 23%) that formed upon coolingby filtration. This material was used without further purification.

Part C. 3-Ethyl-5-methyl(1-[4-Methoxyphenyl]-4-azido)pyrazole-3,5-dicarboxylate.

3-Ethyl-5-methyl (1-[4-Methoxyphenyl]-4-amino)pyrazole-3,5-dicarboxylate(41.0 g, 128.4 mmol) was dissolved in TFA and cooled to 0° C. followedby the portionwise addition of NaNO₂ (10.6 g, 154.1 mmol) and then thereaction was stirred at that temperature for 45 min. NaN₃ (10.0 g, 154.1mmol) was dissolved in a minimal amount of water and added in portionsto the TFA solution. The solution was allowed to stir at 0° C. for 45min and added slowly to a saturated aqueous solution of NaHCO₃. Thesolution was diluted with ethyl acetate and washed twice with brine. Theorganics were dried over MgSO₄1 filtered through a plug of silica geland the volatiles were removed. The residue was recrystallized fromether/hexanes to give the title compound as a tan solid (39.9 g, 90%).LRMS (ES⁺): 346.1 (M+H)⁺.

Part D. (1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-47azido)pyrazole-5-carboxylic acid.

To a solution of 3-ethyl-5-methyl(1-[4-Methoxyphenyl]-4-azido)pyrazole-3,5-dicarboxylate (14.0 g, 40.5mmol) in 50 mL of tetrahydrofuran and 50 mL of water was added lithiumhydroxide (0.97 g, 40.5 mmol) and the reaction was stirred at ambienttemperature for several hours. The reaction was diluted with water andhexanes and made basic with saturated aqueous sodium bicarbonate. Theorganic layer was separated. The aqueous layer was acidified withaqueous HCl and then was extracted with ethyl acetate. The organics werewashed with brine, dried over MgSO₄, and concentrated to afford 10.1 g(75%) of the title compound that was used without purification. LRMS(ES⁺): 332.1 (M+H)⁺.

Part E.1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of(1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-4-azido)pyrazole-5-carboxylicacid (1.50 g, 4.52 mmol) in 20 mL of CH₂Cl₂ was added oxallyl chloride(0.60 mL, 6.80 mmol) and 1 drop of DMF. The mixture was allowed to stirat room temperature for 2 hours. The volatiles were removed underreduced pressure and the residue dried under high vacuum for 1 hour. Theresidue was dissolved in CH₂Cl₂ followed by the addition of DMAP (1.38g, 11.3 mmol) and 4-(2-methylimidazol-1′-yl) aniline (0.78 g, 4.52 mmol)and the solution stirred overnight at room temperature. The volatileswere removed under vacuum and the residue was taken up in ethyl acetateand filtered through a plug of silica gel. The product was obtained byflushing the silica gel with methanol. The volatiles were removed undervacuum and the residue was used without further purification. The crudeproduct was dissolved in ethanol and then there was added tin (II)chloride dihydrate (2.57 g, 13.6 mmol) and the solution was warmed for15 minutes. The solution was diluted with ethyl acetate, washed with 10%aqueous sodium hydroxide and brine, dried MgSO₄) and the volatiles wereremoved under reduced pressure. The residue was refluxed for 2 hours in95% formic acid. The volatiles were removed under reduced pressure andthe residue was purified by reverse phase HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford 0.16 g of the title compound of Example 9 as a white solid.LRMS (ES⁺): 471.2 (M+H)⁺.

Example 101-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 9, Part E (0.50 g, 0.85 mmol) in 20 mL of 1,4-dioxane wasadded 20 mL of aqueous (28%) ammonia and the reaction was stirred atroom temperature overnight. The solution was diluted with EtOAc andwashed with 100 mL of brine. The organics were dried over MgSO₄ and thevolatiles removed under reduced pressure. The residue was purified byreverse phase HPLC (C18 reverse phase column, elution with a H₂O/CH₃CNgradient with 0.5% TFA) and lyophilized to afford the title compound ofExample 10 as a white solid. LRMS (ES⁺): 442.1 (M+H)⁺.

Examples 11 and 121-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt (Example 11) and1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt (Example 12).

Part A.1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-4-azido-5-[4-bromophenylaminocarbonyl]pyrazole.

To a solution of(1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-4-azido)pyrazole-5-carboxylicacid from Example 9, Part D (3.6 g, 10.9 mmol) in 40 mL of CH₂Cl₂ wasadded oxallyl chloride (1.42 mL, 16.3 mmol) and 1 drop of DMF. Themixture was allowed to stir at room temperature for 2 hours. Thevolatiles were removed under reduced pressure and the residue driedunder high vacuum for 1 hour. The residue was dissolved in CH₂Cl₂followed by the addition of DMAP (3.32 g, 27.2 mmol) and 4-bromoaniline(1.86 g, 10.9 mmol) and the solution stirred overnight at roomtemperature. The volatiles were removed under vacuum and the productpurified by trituration of the residue with ether/hexanes to afford thetitle compound (2.6 g, 49%). LRMS (ES⁺): 485.0/487.0 (M+H)⁺.

Part B.1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-4-azido-5-[4-bromophenylaminocarbonyl]pyrazole(2.62 g, 5.40 mmol) in ethanol was added tin (II) chloride dihydrate(3.07 g, 16.2 mmol) and the solution was warmed for 15 minutes. Thesolution was filtered through a pad of silica gel and the silica rinsedwith EtOAc. The volatiles were removed under reduced pressure and theresidue was refluxed for 2 hours in 95% formic acid. The volatiles wereremoved under reduced pressure and the solid residue was washed withcold EtOAc and collected by suction filtration to afford 1.1 g (44%) ofthe title compound as a solid. LRMS (ES⁺): 469.0/471.0 (M+H)⁺.

Part C.1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-formyl-[1,1′-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

A solution of1-[4-methoxyphenyl)-3-(ethoxycarbonyl)-6-[4-bromophenyl]-1,6-dihydropyrazolo-(4,3-d]-pyrimidin-7-one(1.1 g, 2.34 mmol), TBAB (0.07 g, 0.23 mmol), aqueous Na₂CO₃ (2M, 5.0mL, 9.3 mmol), and 2-formylphenylboronic acid (0.49 g, 3.28 mmol) in 30mL of benzene was degassed with a stream of nitrogen for 15 minutes.Following the purge, tetrakis(triphenylphosphine)palladium(0) (0.14 g,0.12 mmol) was added and the solution was stirred overnight at reflux.The solution was diluted with EtOAc, washed twice with brine and driedover MgSO₄, filtered through a pad of silica gel and the volatiles wereremoved under reduced pressure to afford the title compound that wasused without further purification. LRMS (ES⁺): 495.1 (M+H)⁺.

Part D.1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt (Example 11) and1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt (Example 12).

To a solution of1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(2.68 g, 5.42 mmol) in 20 mL of dimethyl formamide was added pyrrolidine(0.77 g, 10.8 mmol) and acetic acid dropwise until pH was about 5-6.Then there was added sodium cyanoborohydride (0.68 g, 10.8 mmol) and theresulting solution was allowed to sir for 18 h. The reaction mixture wasquenched with water and was partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. The organics were washed with water andbrine, dried (MgSO₄) and the volatiles were removed under vacuum. Theresidue was purified by prep HPLC (C18 reverse phase column, elutionwith a H₂O/CH₃CN gradient with 0.5% TFA) to afford 0.3 g (10%) of thetitle compound of Example 11 and 0.5 g (17%) of the title compound ofExample 12. Example 11 LRMS (ES⁺): 550.2 (M+H)⁺. Example 12 LRMS (ES⁺):552.2 (M+H)⁺.

Example 131-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-pyrrolidinylmethyl-1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

To a solution of1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt from Example 11, Part D (0.32 g, 0.48 mmol) in20 mL of 1,4-dioxane was added 20 mL of aqueous (28%) ammonia and thereaction was stirred at room temperature overnight. The solution wasdiluted with EtOAc and washed with 100 mL of brine. The organics weredried over MgSO₄ and the volatiles removed under reduced pressure. Theresidue was purified by reverse phase HPLC (C18 reverse phase column,elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized toafford the title compound of Example 13 as a white solid. LRMS (ES⁺):521.1 (M+H)⁺.

Example 141-[4-methoxyphenyl]-3-cyano-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

To a solution of1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 13 (0.20 g, 32 mmol) in 10 mL of anhydrous benzene wasadded phosphorous oxychloride (0.24 g, 1.57 mmol) and the reaction wasallowed to reflux for 4 hours. The solution was quenched with H₂O andthe volatiles were removed under reduced pressure. The residue waspurified by reverse phase HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford the titlecompound of Example 14 as a white solid. LRMS (ES⁺): 503.1 (M+H)⁺.

Example 151-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-(2-fluoro-4-(2-dimethylaminomethylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

Following the procedures described in Example 9, Part E, the titlecompound of Example 15 was prepared. LRMS (ES⁺): 532.1 (M+H)⁺.

Example 161-[2-aminomethylphenyl]-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

Part A. □-Cyano-.□-(ethoxycarbonyl)-2-methylphenyl hydrazine imine.

To a solution of o-toluidine (20.0 g, 187 mmol) in 320 mL of water at 0°C. was added of 44 mL of concentrated HCl followed by sodium nitrite(16.7 g, 243 mmol) portionwise. The solution was stirred for 15 minutesand then poured into a flask containing a solution of ethyl cyanoacetate(21.1 g, 187 mmol) and sodium acetate trihydrate (55.9 g, 410 mmol) in100 mL of methanol and 200 mL of water at 0° C. A heavy yellowprecipitate immediately formed. After 30 minutes the solid was filtered,washed with water and dried under vacuum to afford 32.4 g (75%) of thetitle compound, that was used without further purification. ¹H NMR(CDCl₃): □ 9.29 (broad S, 1H), 7.63 (d, 1H), 7.28 (t, 1H), 7.20 (d, 1H),7.11 (t, 1H), 4.40 (q, 2H), 2.40 (s, 3H), 1.40 (t, 3H)

Part B.3-Ethyl-5-methyl1-(2-methylphenyl)-4-aminopyrazole-3,5-dicarboxylate.

□-Cyano-.□(ethoxycarbonyl)-2-methylphenyl hydrazine imine (14.0 g, 60mmol), methyl bromoacetate (8.6 mL, 91 mmol) and potassium carbonate(31.3 g, 226 mmol) were dissolved in 150 mL of N,N-dimethyl formamideand heated to 100° C. for several hours. The solution was diluted withethyl acetate and washed 4 times with brine. The organics were driedover MgSO₄, filtered through a pad of silica gel and the volatiles wereremoved. The residue was purified by flash chromatography (elution with3:1 hexanes/ethyl acetate) to afford 5.15 g (28%) of the title compound.¹H NMR (CDCl₃): □ 7.30-7.15 (m, 4H), 5.25 (broad s, 2H), 4.40 (q, 2H),3.67 (s, 3H), 2.01 (s, 3H), 1.38 (t, 3H).

Part C.1-(2-methylphenyl)-3-(ethoxycarbonyl)-4-azidopyrazole-5-carboxylic acid.

3-Ethyl-5-methyl 1-(2-methylphenyl)-4-aminopyrazole-3,5-dicarboxylate(5.2 g, 17.0 mmol) was dissolved in 100 mL of TFA and cooled to 0° C.followed by the addition of NaNO₂ (1.4 g, 20.4 mmol) and then thereaction was stirred at that temperature for 45 min. Sodium azide (1.3g, 20.4 mmol) was dissolved in a minimal amount of water and added inportions to the TFA solution. The solution was allowed to stir at 0° C.for 45 min and added slowly to a saturated aqueous solution of NaHCO₃.The solution was diluted with ethyl acetate and washed twice with brine.The organics were dried over MgSO₄, filtered through a plug of silicagel and the volatiles were removed. The residue was triturated withether to afford a crude azide that was used without purification.

To a solution of 1.0 g (3.0 mmol) of the residue in 20 mL oftetrahydrofuran and 20 mL of water was added lithium hydroxide (60 mg,2.7 mmol) and the reaction was stirred at ambient temperature forseveral hours. The reaction was diluted with water and hexanes and madebasic with saturated aqueous sodium bicarbonate. The organic layer wasseparated. The aqueous layer was acidified with aqueous HCl and then wasextracted with ethyl acetate. The organics were washed with brine, driedover MgSO₄, and concentrated to afford 0.65 g (69%) of the titlecompound that was used without purification. LRMS (ES−): 314.2 (M−H)⁺.

Part D.1-(2-methylphenyl)-3-(ethoxycarbonyl)-4-azido-5-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole.

To a solution of1-(2-methylphenyl)-3-(ethoxycarbonyl)-4-azidopyrazole-5-carboxylic acid(0.69 g, 2.2 mmol) in 50 mL of CH₂Cl₂ was added oxallyl chloride (0.29mL, 3.3 mmol) and 1 drop of DMF. The mixture was allowed to stir at roomtemperature for 2 hours. The volatiles were removed under reducedpressure and the residue dried under high vacuum for 1 hour. The residuewas dissolved in CH₂Cl₂ followed by the addition of DMAP (0.81 g, 6.6mmol) and [2′-methylsulfonyl-[1,1′]-biphen-4-yl]amine hydrochloride(0.62 g, 2.2 mmol) and the solution was stirred overnight at roomtemperature. The volatiles were removed under vacuum and the residue wastaken up in ethyl acetate, washed with saturated aqueous sodiumbicarbonate and brine, dried (MgSO₄) and filtered through a plug ofsilica gel. The volatiles were removed under vacuum to afford 1.0 g(83%) of the title compound that was used without further purification.LRMS (ES−): 543.1 (M−H)⁻.

Part E.1-(2-methylphenyl)-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-(2-methylphenyl)-3-(ethoxycarbonyl)-4-azido-5-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole(0.98 g, 1.8 mmol) in absolute ethanol was added tin (II) chloridedihydrate (1.22 g, 5.4 mmol) and the solution was warmed for 15 minutes.The solution was filtered through a pad of silica gel and the silicarinsed with EtOAc. The volatiles were removed under reduced pressure andthe residue was refluxed for 2 hours in 95% formic acid. The volatileswere removed under reduced pressure and the solid residue was purifiedby flash chromatography (elution with 1:1 hexanes/ethyl acetate) toafford 0.21 g (22%) of the title compound as a solid. LRMS (ES⁺): 529.2(M+H)⁺.

Part F.1-[2-bromomethylphenyl]-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-(2-methylphenyl)-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.21 g, 0.4 mmol) in 50 mL of carbon tetrachloride was addedN-bromosuccinimide (0.08 g, 0.44 mmol) and a small amount of AIBN. Thereaction was stirred at reflux for 5 h and then was cooled and dilutedwith ethyl acetate. The organics were washed with brine, dried (MgSO₄)and concentrated in vacuo to afford 0.24 g (99%) of the title compoundthat was used without purification. LRMS (ES⁺): 607.0/609.0 (M+H)⁺.

Part G.1-[2-aminomethylphenyl]-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

To a solution of1-[2-bromomethylphenyl]-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.24 g, 0.4 mmol) in 20 mL of dimethyl formamide was added sodium azide(0.04 g, 0.6=mol) and the reaction was stirred at ambient temperaturefor 3 h. The reaction was poured into water and extracted with ethylacetate. The organics were washed with brine, dried (MgSO₄) andconcentrated in vacuo to afford 0.21 g (91%) of an azide that was usedwithout further purification. This azide was taken up in 20 mL ofabsolute ethanol and 10 mL of tetrahydrofuran and then there was addedtin (II) chloride dihydrate (0.061 g, 0.27 mmol). The reaction wasallowed to stir at reflux for 18 h. The voltiles were removed in vacuoand the residue was purified by prep HPLC (C18 reverse phase column,elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized toafford the title compound of Example 16 as a white solid. LRMS (ES⁺):544.2 (M+H)⁺.

Example 171-[3-aminoiminomethylphenyl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A. 1-[4-bromophenyl]-4-acetyl-2,3-dioxopiperidine.

This intermediate was prepared in four steps in 10% overall yield by thefollowing sequence of reactions. Commercially available 4-bromoanilinewas treated with commercially available 5-chloro-2-pentanone ethyleneketal in dimethylformamide in the presence of potassium carbonate forthree days. The crude alkylated aniline was treated with ethyloxalylchloride in THF the presence of triethylamine. Hydrolysis of the ketalwas accomplished by treating with aqueous HCl and the resulting materialwas subjected to Dieckmann cyclization conditions (NaOMe, methanol). Thecrude dioxopiperidine was purified by flash chromatography (elution with4:1 hexanes/ethylacetate) to afford the title compound. ¹H NMR (dmsod6): □ 7.56 (d, 2H, J=8 Hz), 7.26 (d, 2H, J=8 Hz), 3.60 (t, 2H), 3.28(t, 2H), 2.30 (s, 3H). LRMS (ES⁺): 281.0 (M+H)⁺.

Part B.1-[3-aminoiminomethylphenyl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt.

To a solution of 1-[4-bromophenyl]-4-acetyl-2,3-dioxopiperidine inglacial acetic acid was added 3-cyanophenyl hydrazine. The reactionmixture was stirred at reflux for 3 h and then was cooled to ambienttemperature. The volatiles were removed and the residue was taken up inethyl acetate. The organics were washed with saturated aq sodiumbicarbonate and brine, dried (MgSO₄) and concentrated.

The residue was dissolved in benzene and then there was addedtetrabutylammonium bromide, aqueous Na₂CO₃ and2-(tert-butylaminosulfonyl)phenylboronic. This solution was degassedwith a stream of nitrogen for 30 minutes. Following the purge,tetrakis(triphenylphosphine)palladium(0) was added and the solution wasstirred overnight at reflux. The solution was diluted with EtOAc andwashed twice with brine and the organics dried over MgSO₄, filtered andthe volatiles removed under reduced pressure. The residue was purifiedby column chromatography (elution with 1:1 hexane/EtOAc) to afford anintermediate biphenyl compound.

This material was dissolved in 50 mL of anhydrous methanol and wascooled to 0° C. Anhydrous HCl gas was bubbled through the solution forabout 30 min (until solution saturated). The flask was then sealed andallowed to stand for 16 h at 0° C. The reaction mixture was concentratedin vacuo. The resulting solid was dissolved in anhydrous methanol andammonium carbonate was added and the mixture was allowed to stir at roomtemperature for 24 h. The reaction mixture was concentrated in vacuo.The residue was dissolved in trifluoroacetic acid and stirred at refluxfor 20 minutes. The volatiles were removed in vacuo and the residue waspurified by prep HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford the titlecompound of Example 17 as a white powder. ¹H NMR (dmso d6): □ 9.40(broad s, 1.5H), 9.28 (broad s, 1.5H), 8.04 (ds, 2H), 7.94 (d, 1H), 7.81(d, 1H), 7.78-7.48 (m, 4H), 7.40-7.30 (m, 4H), 4.18 (t, 2H), 2.95 (t,2H), 2.30 (s, 3H). LRMS (ES⁺): 501.0 (M+H)⁺.

Example 181-[2-aminomethylphenyl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A.1-[2-trifluoroacetamidomethylphenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

To solution of 2-(trifluoroacetamidomethyl) aniline (6.5 g, 0.029 mol),prepared from 2-(aminomethyl) aniline and ethyl trifluoroacetate, wasadded conc. HCl (50 mL) with cooling in an ice bath. The temperature wasmaintained between 0° C. and 100° C. and sodium nitrite (2 g, 0.029 mol)in water (40 mL) was added. The diazonium was stirred cold for 2 h, thenstannous chloride dihydrate (15.4 g, 0.069 mol) in conc. HCl (5 mL) andwater (50 mL) was added slowly. The reaction was stirred 0.5 h,saturated with NaCl, extracted with ether, dried (Na₂SO₄) andconcentrated. A portion of the crude hydrazine tin salt (2 g) wascombined with 1-[4-bromophenyl]-4-acetyl-2,3-dioxopiperidine fromExample 17, Part A (0.46 g, 1.5 mmol) and acetic acid (20 mL) and heatedto reflux for 8 h. The reaction was concentrated, taken up in ethylacetate, washed successively with sat'd NaHCO₃ and sat'd NaCl, dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography (elution with 1:1 hexanes/ethyl acetate) to afford 0.24 g(32%) of the title compound as a yellow oil. LRMS (ES+): 507/509 (M+H)⁺.

Part B.1-[2-aminomethylphenyl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt.

To a solution of1-[2-trifluoroacetamidomethylphenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(0.24 g, 0.47 mmol) in dioxane (15 mL) was added 2-tert-butylsulfonamidebenzeneboronic acid (0.16 g, 0.62 mmol), potassium phosphate tribasic(0.3 g, 1.4 mmol), and the mixture was degassed with N₂ for 0.5 h.Tetrakis(triphenylphosphine)palladium(0) (50 mg) was added and thereaction was heated to reflux for 4 h. The reaction was filtered throughCelite® and the filtrate concentrated. Trifluoroacetic acid (10 mL) wasadded to the crude residue and the mixture was heated to reflux for 0.25h. The reaction was concentrated and the residue was purified by flashchromatography (elution with 2:1 hexanes/ethyl acetate) to afford 0.13 g(49%) of the trifluoroacetamide as a tan foam. The trifluoroacetamidewas placed in MeOH (10 mL), water (2 mL) and K₂CO₃ (0.15 g) and heatedto reflux for 4 h. The reaction was concentrated, acidified with TFA,purified by prep HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford the titlecompound of Example 18 as a white powder. ¹H NMR (DMSO-d6) □ 8.19 (broads, 2H), 8.05 (dd, J=1.1, 7.4 Hz, 1H), 7.65-7.28 (m, 13H), 4.17 (t, J=6.6Hz, 2H), 3.88 (m, 2H), 3.01 (t, J=6.2, 2H), 2.31 (s, 3H). LRMS (ES⁺):488.3 (M+H)^(t).

Example 191-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

Part A.1-[3-cyano-4-fluorophenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

To 1-[4-bromophenyl]-4-acetyl-2,3-dioxopiperidine from Example 17, PartA (0.3 g, 0.97 mmol) in acetic acid (20 mL) was added3-cyano-4-fluorophenylhydrazine stannyl chloride hydrochloride (0.39 g,1.16 mmol) and the mixture was heated to reflux for 8 h. The reactionwas concentrated, taken up in ethyl acetate, washed successively withsat'd NaHCO₃ and sat'd NaCl, dried (Na₂SO₄) and concentrated.Purification by silica gel chromatography using 1:1 hexanes/ethylacetate as eluent afforded 0.31 g (76%) of the title compound as a whitesolid. ¹H NMR (CDCl₃) □ 7.88 (m, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.25 (m,1H), 7.21 (d, J=8.4 Hz, 2H), 4.13 (t, J=7.0 Hz, 2H), 2.98 (t, J=6.6 Hz,2H), 2.35 (s, 3H). LRM (ES⁺): 425.1/427.1 (M+H)⁺.

Part B.1-[3-cyano-4-fluorophenyl]-3-methyl-6-[2-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

To a solution of1-[3-cyano-4-fluorophenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(0.31 g, 0.73 mmol) in 15 mL of dioxane was added2-tert-butylsulfonamide benzeneboronic acid (0.24 g, 0.95 mmol),potassium phosphate tribasic (0.47 g, 2.2 mmol), and the mixture wasdegassed with N₂ for 0.5 h. Tetrakis(triphenylphosphine)palladium(0) (60mg) was added and the reaction was heated in a 70-80° C. bath for 18 h.The reaction was filtered through Celite® and the filtrate concentrated.Purification by silica gel chromatography using 1:1 hexanes/ethylacetate as eluent afforded 0.24 g (59%) of a yellow solid. ¹H NMR(CDCl₃): □ 8.18 (dd, J=1.4, 7.7 Hz, 1H), 7.91 (m, 2H), 7.59 (m, 4H),7.42 (d, J=8.4 Hz, 2H), 7.32 (dd, J=1.5, 7.5 Hz, 1H), 7.24 (d, J=8.8 Hz,1H), 4.19 (t, J=6.5 Hz, 2H), 3.68 (s, 1H), 3.68 (t, J=6.9 Hz, 2H), 2.36(3H, s), 1.04 (s, 9H). LRMS (ES⁺): 580.3 (M+Na)⁺.

Part C.1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

Trifluoroacetic acid (10 mL) was added to1-[3-cyano-4-fluorophenyl]-3-methyl-6-[2′-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-oneand the mixture was heated to reflux for 0.25 h. The reaction wasconcentrated and the residue dried in vacuo for 2 h. To the cruderesidue was added DMF (5 mL), K₂CO₃ (0.18 g, 1.3 mmol), andacetohydroxamic acid (97 mg, 1.3 mmol) and the reaction was stirred atambient temperature. After 0.25 h excess K₂CO₃ and acetohydroxamic acidwere added to counter residual TFA and the rection was stirred 18 h.Water (10 mL) was added and the precipitate filtered off. The solid wasacidifed in TFA/CH₃CN, concentrated and purified by prep HPLC (C18reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA)and lyophilized to afford the title compound of Example 19 as a whitepowder. LRMS (ES⁺): 515.2 (M+H)⁺, 537 (M+Na)⁺.

Example 201-[4-methoxyphenyl]-3-cyano-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt.

Part A.1-[4-methoxyphenyl]-3-cyano-4-azido-5-[4-bromophenylaminocarbonyl]pyrazole.

1-[4-Methoxyphenyl]-3-cyano-4-azidopyrazole-5-carboxylic acid fromExample 2, Part A (2.92 g, 10.3 mmol) was dissolved in CH₂Cl₂ followedby the addition of oxalyl chloride (1.34 mL, 15.4 mmol) and 2 drops ofDMF. The mixture was allowed to stir at room temperature for 2 hrs. Thevolatiles were removed under reduced pressure and the residue driedunder high vacuum for 1 hr. The residue was dissolved in CH₂Cl₂ followedby the addition of DMAP (3.78 g, 30.9 mmol) and 4-bromo-aniline (1.77 g,10.3 mmol) and the solution stirred overnight at room temperature. Thereaction mixture was diluted with ethyl acetate, washed sequentiallywith 10% aqueous HCl, saturated aqueous sodium bicarbonate and brine,dried (MgSO₄) and filtered through a plug of silica gel. The volatileswere removed under vacuum to afford 3.9 g (87%) of the title compoundthat was used without further purification. ¹H NMR (CDCl₃)-8.41 (broads, 1H), 7.43 (app s, 4H), 7.31 (d, 2H), 6.98 (d, 2H), 3.86 (s, 3H).

Part B.1-[4-methoxyphenyl]-3-cyano-4-amino-5-[4-bromophenyl)aminocarbonyl]pyrazole.

To a solution of1-[4-methoxyphenyl]-3-cyano-4-azido-5-[4-bromophenylaminocarbonyl]pyrazole(3.9 g, 8.9 mmol) in 30 mL of isopropanol was added tin (II) chloridedihydrate (8.0 g, 35.6 mmol) and the solution was stirred at 80° C. for2 hrs. The solution was cooled, dissolved in EtOAc, washed with 10%aqueous NaOH solution and brine, dried over MgSO₄, filtered through apad of silica gel and dried under vacuum to give the title compound (3.0g, 82%). ¹H NMR (dmso-D6) n 10.26 (s, 1H), 7.46 (app s, 4H), 7.35(d,2H), 6.98 (d, 2H), 5.46 (broad s, 2H), 3.74 (s, 3H).

Part C.1-[4-methoxyphenyl]-3-cyano-6-[4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

1[4-methoxyphenyl]-3-cyano-4-amino-5-[4-bromophenylaminocarbonyl]pyrazole(0.60 g, 1.45 mmol) was dissolved in 5 mL of N,N-dimethylformamidedimethyl acetal and stirred at 100° C. for 1 h. The volatiles wereremoved and the residue was dissolved in 95% formic acid and stirred at100° C. for 1 h. The volatiles were removed in vacuo and the residue wasdissolved in EtOAc and washed with saturated NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered through a plug of silica geland the volatiles were removed to yield the title compound as anoff-white solid (0.56 g, 91%). ¹H NMR (dmso-D6) □ 8.45 (s, 1H), 7.75(app d, 2H), 7.62(app d, 2H), 7.45 (app d, 2H), 7.05 (app d, 2H), 3.79(s, 3H).

Part D.1-[4-methoxyphenyl]-3-cyano-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-cyano-6-[4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.40 g, 0.95 mmol) in 10 mL of 1,4-dioxane was added2-formylphenylboronic acid (0.22 g, 1.43 mmol) and potassium phosphatetribasic (0.71 g, 3.33 mmol). This mixture was degassed with a stream ofnitrogen for 15 minutes. Following the purge,tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.035 mmol) was addedand the solution was stirred overnight at 100° C. The solution wascooled, diluted with EtOAc, washed twice with brine and the organicswere dried over MgSO₄, filtered through a pad of silica gel andconcentrated to afford 0.30 g (71%) of the title compound that wassufficiently pure to be used without purification. ¹H NMR (CDCl₃) □10.02 (s, 1H), 8.21 (s, 1H), 8.06 (dd, 1H), 7.70-7.40 (m, 9H), 7.00 (appd, 2H), 3.86 (s, 3H).

Part E.1-[4-methoxyphenyl]-3-cyano-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-cyano-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.30 g, 0.67 mmol) in 10 mL of 1:1 DMF/THF was added sodium borohydride(38 mg, 1.0 mmol) and the reaction was stirred at ambient temperaturefor 1 h. The reaction was quenched with 10% aqueous HCl and then dilutedwith ethyl acetate. The organics were washed with water and brine, dried(MgSO₄) and concentrated. The residue was purified by flashchromatography (elution with 2:1 hexanes/ethyl acetate) to afford 150 mg(50%) of the title compound. ¹H NMR (dmso-D6)□ 8.53 (s, 1H), 7.65 (appd, 2H), 7.62-7.54 (m, 5H), 7.42-7.30 (m, 2H), 7.23 (dd, 1H), 7.07 (appd, 2H), 5.19 (t, 1 h), 4.39 (s, 2H), 3.80 (s, 3H).

Part F.1-[4-methoxyphenyl]-3-cyano-6-[2′-N,N-dimethyaminomethyl-[1,1′-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt.

To a solution of1-(4-methoxyphenyl]-3-cyano-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(120 mg, 0.27 mmol) in 5 mL of CH₂Cl₂ was added phosphorous tribromide(144 mg, 0.53 mmol) and the reaction mixture was allowed to stir atambient temperature for 1 h. The reaction was diluted with ethylacetate, washed with brine, dried (MgSO₄), filtered through a pad ofsilica gel and concentrated to afford 115 mg of a crude bromide. To aportion of this residue (65 mg, 0.13 mmol) in 2 mL of acetonitrile wasadded dimethylamine (0.13 mL of a 2M solution in methanol, 0.26 mmol).The reaction was allowed to stir at ambient temperature for 2 h. Thereaction was concentrated and the residue was purified by prep HPLC (C18reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA)and lyophilized to afford 38 mg (50%) of the title compound of Example20 as a white powder. ¹H NMR (dmso-D6)□ 9.68 (broad s, 1H), 8.48 (s,1H), 7.72-7.50 (m, 9H), 7.36 (dd, 1H), 7.07 (app d, 2H), 4.30 (broad s,2H), 3.80 (s, 3H), 2.55 (s, 6H). LRMS (ES⁺): 477.3 (M+H)⁺.

Example 211-[4-methoxyphenyl]-3-cyano-5-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

Part A.1-[4-methoxyphenyl]-3-cyano-5-methyl-6-[4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

1-[4-methoxyphenyl]-3-cyano-4-amino-5-[4-bromophenyl)aminocarbonyl]pyrazolefrom Example 20, Part B (1.0 g, 2.4 mmol) was dissolved in 5 mL ofN,N-dimethylacetamide dimethyl acetal and stirred at 100° C. for 1 h.The volatiles were removed and the residue was dissolved in glacialacetic acid and stirred at 100° C. for 1 h. The volatiles were removedin vacuo and the residue was dissolved in EtOAc and washed withsaturated NaHCO₃ and brine. The organics were dried over MgSO₄, filteredthrough a plug of silica gel and the volatiles were removed to yield thetitle compound as an off-white solid (0.95 g, 90%). ¹H NMR (dmso-D6) □7.75 (app d, 2H), 7.58 (app d, 2H), 7.37 (app d, 2H), 7.04 (app d, 2H),3.78 (s, 3H), 2.15 (s, 3H).

Part B.1-[4-methoxyphenyl]-3-cyano-5-methyl-6-[2′-formyl-[1,1′-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d3-pyrimidin-7-one.

To a solution of1-[4-methoxyphenyl]-3-cyano-6-[4-bromophenyl]-1,6-dihydropyrazolo-[4,3-d]-5-methyl-pyrimidin-7-one(0.24 g, 0.55 mmol) in 10 mL of 1,4-dioxane was added2-formylphenylboronic acid (0.12 g, 0.83 mmol) and potassium phosphatetribasic (0.41 g, 1.93 mmol). This mixture was degassed with a stream ofnitrogen for 15 minutes. Following the purge,tetrakis(triphenylphosphine)palladium(0) (0.025 g) was added and thesolution was stirred at 100° C. for 4 h. The solution was cooled,diluted with EtOAc, washed twice with brine and the organics were driedover MgSO₄, filtered through a pad of silica gel and concentrated. Theresidue was purified by flash chromatography (elution with 2:1hexanes/ethyl acetate) to afford 0.10 g (40%) of the title compound. ¹HNMR (CDCl₃) □ 10.02 (s, 1H), 8.05 (dd, 1H), 7.69 (td, 1H), 7.65-7.55 (m,5H), 7.46 (dd, 1H), 7.36 (app d, 2H), 6.98(app d, 2H), 3.83 (s, 3H),2.38 (s, 3H).

Part C.1-[4-methoxyphenyl]-3-cyano-5-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d3-pyrimidin-7-onetrifluoroacetic acid salt.

To a solution of1-[4-methoxyphenyl]-3-cyano-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-5-methyl-pyrimidin-7-one(80 mg, 0.17 mmol) in 5 mL of THF was added dimethylamine (0.34 mL of a2M solution in methanol, 0.68 mmol) and then sodiumtriacetoxyborohydride (73 mg, 0.35 mmol) and 2 drops of glacial aceticacid. The reaction was allowed to stir at ambient temperature for 3 h.The reaction was quenched with water and diluted with ethyl acetate andsaturated aqueous NaHCO₃. The organics were washed with brine, dried(MgSO₄) and concentrated. The residue was purified by prep HPLC (C18reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA)and lyophilized to afford 45 mg (44%) of the title compound of Example21 as a white powder. ¹H NMR (dmso-D6) □ 9.60 (broad s, 1H), 7.70 (m,1H), 7.60 (app d, 2H), 7.65-7.48 (m, 6H), 7.39 (m, 1H), 7.05 (app d,2H), 4.31 (broad s, 2H), 3.79 (s, 3H), 2.53 (s, 6H), 2.24 (s, 3H). LRMS(ES⁺): 491.3 (M+H)⁺.

Example 221-[2-aminomethylphenyl]-3-cyano-6-[2-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

Part A. □.□-Dicyano-2-methylphenyl hydrazine imine.

To a solution of o-toluidine (10.0 g, 93.3 mmol) in 160 mL of water at0° C. was added of 22 mL of concentrated HCl followed by sodium nitrite(8.4 g, 121 mmol) portionwise. The solution was stirred for 15 minutesand then poured into a flask containing a solution of malononitrile (6.2g, 93.3 mmol) and sodium acetate trihydrate (28 g, 205 mmol) in 50 mL ofmethanol and 100 mL of water at 0° C. A heavy yellow precipitateimmediately formed. After 30 minutes the solid was filtered, washed withwater and dried under vacuum to afford 16 g (93%) of the title compound,that was used without further purification. ¹H NMR (CDCl₃):⁻ 9.60 (broads, 1H), 7.53 (d, 1H), 7.31 (t, 1H), 7.22 (m, 2H), 2.40 (s, 3H).

Part B. Methyl1-(2-methylphenyl)-3-cyano-4-aminopyrazole-5-carboxylate.

□,□-Dicyano-2-methylphenyl hydrazine imine (12.0 g, 65.1 mmol), methylbromoacetate (9.3 mL, 97.7 mmol) and potassium carbonate (22.5 g, 163mmol) were dissolved in 100 mL of N,N-dimethyl formamide and heated to100° C. for 3 h. The solution was cooled, diluted with ethyl acetate andwashed 2 times with brine. The organics were dried over MgSO₄, filteredthrough a pad of silica gel and the volatiles were removed. The residuewas purified by flash chromatography (elution with 3:1 hexanes/ethylacetate) to afford 5.1 g (31%) of the title compound. ¹H NMR (CDCl₃): □7.39 (t, 1H), 7.28 (m, 2H), 7.17 (d, 1H), 3.71 (s, 3H), 2.04 (s, 3H).LRMS (ESI): 255.1 (M−H)—.

Part C. 1-(2-methylphenyl)-3-cyano-4-azidopyrazole-5-carboxylic acid.

To a solution of methyl1-(2-methylphenyl)-3-cyano-4-aminopyrazole-5-carboxylate (5.1 g, 19.9mmol) in 100 mL of TFA at 0° C. was added NaNO₂ (1.65 g, 23.9 mmol) andthen the reaction was stirred at that temperature for 45 min. Sodiumazide (1.55 g, 23.9 mmol) was dissolved in a minimal amount of water andadded in portions to the TFA solution. The solution was allowed to stirat 0° C. for 45 min and added slowly to a saturated aqueous solution ofNaHCO₃. The solution was diluted with ethyl acetate and washed twicewith brine. The organics were dried over MgSO₄, filtered through a plugof silica gel and the volatiles were removed to afford 5.26 g of crudeazide that was used without purification. To a solution of crude azide(5.26 g, 18.6 mmol) in 100 mL of tetrahydrofuran and 50 mL of water at0° C. was added lithium hydroxide (0.53 g, 22.3 mmol) and the reactionwas stirred at ambient temperature for 3 h. The reaction was dilutedwith water and ethyl acetate and made basic with saturated aqueoussodium bicarbonate. The organic layer was separated. The aqueous layerwas acidified with aqueous HCl and then was extracted with ethylacetate. The organics were washed with brine, dried over MgSO₄, andconcentrated to afford 5.18 g of the title compound that was usedwithout purification. ¹H NMR (CDCl₃): _(—)9.56 (broad s, 1H), 7.42 (t,1H), 7.30 (m, 2H), 7.15(d, 1H), 2.03 (s, 3H).

Part D.1-(2-methylphenyl)-3-cyano-4-azido-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole.

To a solution of 1-(2-methylphenyl)-3-cyano-4-azidopyrazole-5-carboxylicacid (2.25 g, 8.37 mmol) in 50 mL of CH₂Cl₂ was added oxalyl chloride(1.1 mL, 12.6 mmol) and 2 drops of DMF. The mixture was allowed to stirat room temperature for 2 hours. The volatiles were removed underreduced pressure and the residue dried under high vacuum for 1 hour. Theresidue was dissolved in CH₂Cl₂ followed by the addition of DMAP (3.07g, 25.1 mmol) and [2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminehydrochloride (2.53 g, 8.37 mmol) and the solution was stirred overnightat room temperature. The volatiles were removed under vacuum and theresidue was taken up in ethyl acetate, washed with 10% aqueous HCl,saturated aqueous sodium bicarbonate and brine, dried (MgSO₄) andfiltered through a plug of silica gel. The volatiles were removed undervacuum to afford 4.1 g (95%) of the title compound that was used withoutfurther purification. ¹H NMR (CDCl₃): □ 8.94 (d, 1H), 8.30 (t, 1H), 8.20(dd, 1H), 7.64 (td, 1H), 7.57 (td, 1H), 7.46 (t, 1H), 7.37-7.30 (m, 4H),7.23 (m, 1H), 7.13 (d, 1H), 2.68 (s, 3H), 2.08 (s, 3H).

Part E.1-(2-methylphenyl)-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-(2-methylphenyl)-3-cyano-4-azido-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole(2.06 g, 4.0 mmol) in absolute ethanol was added tin (II) chloridedihydrate (2.71 g, 12.0 mmol) and the solution was stirred at reflux for2 h. The reaction was cooled and concentrated. The residue was taken upin ethyl acetate, washed with dilute aqueous sodium hydroxide and brine,dried (MgSO₄) and concentrated. The residue was dissolved in 25 mL ofN,N-dimethylformamide dimethyl acetal and stirred at 100° C. for 2 h.The reaction was cooled and concentrated in vacuo. The residue was takenup in 95% formic acid and stirred at 100° C. for 2 h. The reaction wascooled and concentrated. The residue was diluted with ethyl acetate andwashed with saturated NaHCO₃ and brine, dried (MgSO₄) and concentratedto afford 0.60 g (30%) of the title compound that was used withoutpurification. ¹H NMR (CDCl₃): □ 8.23 (dd, 1H), 8.13 (s, 1H), 7.67 (symmm, 2H), 7.50-7.30 (m, 8H), 2.76 (s, 3H), 2.17 (s, 3H).

Part F.1-[2-aminomethylphenyl]-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt.

To a solution of1-(2-methylphenyl)-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.30 g, 0.60 mmol) in 50 mL of 1,2-dichloroethane was addedN-bromosuccinimide (0.13 g, 0.72 mmol) and a small amount of AIBN. Thereaction was stirred at reflux for 16 h and then was cooled and dilutedwith ethyl acetate. The organics were washed with brine, dried (MgSO₄)and concentrated in vacuo to afford 0.35 g of a 4:1 mixture of desiredbromide/starting material that was used without purification.

To this residue in 20 mL of dimethyl formamide was added sodium azide(0.06 g, 0.9 mmol) and the reaction was stirred at ambient temperaturefor 16 h. The reaction was poured into water and extracted with ethylacetate. The organics were washed with brine, dried (MgSO₄) andconcentrated in vacuo to afford 0.21 g (91%) of an azide that was usedwithout further purification. This azide was taken up in 20 mL ofisopropanol and 10 mL of tetrahydrofuran and then there was added tin(II) chloride dihydrate (0.41 g, 1.8 mmol). The reaction was allowed tostir at reflux for 18 h. The volatiles were removed in vacuo and theresidue was purified by prep HPLC (C18 reverse phase column, elutionwith a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford thetitle compound of Example 22 as a white solid. ¹H NMR (dmso-D6) □ 8.66(s, 1H), 8.21 (broad s, 3H), 8.09 (dd, 1H), 7.80-7.50 (m, 8H), 7.42 (m,2H), 3.99 (broad s, 2H), 2.94 (s, 3H). LRMS (ES⁺): 515.1 (M+H)⁺.

Example 231-[4-methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one.

Part A. Ethyl1-[4-methoxyphenyl]-3-trifluoromethyl-4-acetylpyrazole-5-carboxylate.

To a solution of □bromo-□-.□-trifluoromethyl-4-methoxyphenyl hydrazineimine (2.0 g, 6.7 mmol) in 200 mL of absolute ethanol was added ethyl2,4-dioxovalerate (2.33 g, 14.7 mmol) and sodium ethoxide (5.0 mL of a21% wt solution in ethanol, 13.4 mmol). The reaction mixture was stirredat ambient temperature overnight. The ethanol was removed and theresidue was diluted with ethyl acetate, washed sequentially with 10% aqHCl, sat'd aq NaHCO₃ and brine, dried (MgSO₄) and concentrated. Theresidue was purified by flash chromatography (elution with 4:1hexanes/ethyl acetate) to afford 0.48 g (20%) of the title compound. ¹HNMR (CDCl₃): □ 7.37 (d, 2H), 6.97 (d, 2H), 4.27 (q, 2H), 3.85 (s, 3H),2.57 (s, 3H), 1.22 (t, 3H).

Part B.1-[4-methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[4-bromophenyl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one.

To a solution of ethyl1-[4-methoxyphenyl]-3-trifluoromethyl-4-acetylpyrazole-5-carboxylate(1.5 g, 4.2 mmol) in 100 mL of absolute ethanol was added 4-bromophenylhydrazine hydrochloride (0.94 g, 4.2 mmol) and the resulting mixture wasstirred at reflux overnight. Upon cooling a solid fell out of solution.The mixture was filtered and the solid was dried in vacuo to afford 0.77g (38%) of the title compound. ¹H NMR (CDCl₃): □ 7.60-7.45 (m, 6H), 7.00(d, 2H), 3.85 (s, 3H), 2.69 (s, 3H).

Part C.1-[4-methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one.

To a solution of1-[4-methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[4-bromophenyl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one(0.10 g, 0.21 mmol) in 20 mL of benzene was added2-(tert-butylaminosulfonyl)phenyl boronic acid (0.08 g, 0.29 mmol),tetrabutylammonium bromide (7 mg, 0.02 mmol), sodium carbonate (0.07 g,0.63 mmol) and 1 mL of water. This mixture was degassed with a stream ofnitrogen for 15 minutes and then there was added tetrakis(triphenylphosphine) palladium (0.02 g, 0.02 mmol). The reaction mixturewas stirred at reflux for 16 h. The mixture was cooled, diluted withethyl acetate and washed with sat'd aq NaHCO₃ and brine, dried (MgSO₄)and concentrated. The residue was taken up in 10 mL of trifluoroaceticacid and stirred at reflux for 30 min and concentrated in vacuo. Theresidue was purified by prep HPLC (C18 reverse phase column, elutionwith a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford thetitle compound of Example 23 as a white solid. ¹H NMR (dmso-D6) □ 8.01(dd, 1H), 7.64-7.56 (m, 3H), 7.49 (m, 4H), 7.34 (m, 2H), 7.05 (d, 2H),3.80 (s, 3H), 2.58 (s, 3H). LRMS (ES⁺): 556.0 (M+H).

Example 241-[4-methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one,trifluoroacetic acid salt.

To a solution of1-[4-methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[4-bromophenyl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-onefrom Example 23, Part B (0.10 g, 0.21 mmol) in 10 mL of toluene and 10mL of water was added 2-formylphenylboronic acid (0.04 g, 0.29 mmol) andpotassium fluoride (0.02 g, 0.42 mmol). This mixture was degassed with astream of nitrogen for 15 minutes and then there was added tetrakis(triphenylphosphine) palladium (0.02 g, 0.02 mmol). The reaction mixturewas stirred at reflux for 16 h. The mixture was cooled, diluted withethyl acetate and washed with sat'd aq NaHCO₃ and brine, dried (MgSO₄)and concentrated to give 0.11 g of an aldehyde. This aldehyde wasdissolved in 10 mL of DMF and then there was added pyrrolidine (0.02 mL,0.26 mmol). This mixture was allowed to stir at ambient temperature for1 h. The pH was adjusted to 6 by addition of acetic acid and then therewas added sodium cyanoborohydride (0.03 g, 0.42 mmol). The reaction wasallowed to stir at ambient temperature overnight. The reaction wasquenched with dilute aq HCl, diluted with ethyl acetate, washed withbrine, dried (MgSO₄) and concentrated. The residue was purified by prepHPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradient with0.5% TFA) and lyophilized to afford the title compound of Example 24 asa white solid. ¹H NMR (dmso-D6) □ 7.72 (m, 1H), 7.70-7.60 (m, 4H), 7.51(m, 2H), 7.46 (d, 2H), 7.35 (m, 1H), 7.06 (d, 2H), 4.39 (broad s, 2H),3.81 (s, 3H), 3.35 (m, 2H), 2.80 (m, 2H), 2.58 (s, 3H), 1.77 (m, 4H).LRMS (ES⁺): 560.2 (M+H)⁺.

Example 251-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[4-(1-methylimidazol-2′-yl)phenyl]-1,6-dihydropyrazolo-14,3-d]-pyrimidin-7-onetrifluoroacetic acid salt

Part A.1-[3-cyano-4-fluorophenyl]-3-trifluoromethyl-4-nitropyrazole-5-carboxylate.

To a solution of1-[3-cyano-4-fluorophenyl)-3-trifluoromethylpyrazole-5-carboxylate (2.30g, 7.7 mmol) in 70 mL of trifluoroacetic acid was added ammonium nitrate(0.92 g, 11.6 mmol). Stirred for 15 minutes and then cooled to 0° C. andadded trifluoroacetic anhydride (5.4 mL, 38.5 mmol). The reaction wasallowed to stir overnight with warming to room temperature. The reactionwas concentrated, poured into water, diluted with ethyl acetate, washedwith saturated NaHCO₃ and brine, dried (MgSO₄) and concentrated. Theresidue was a mixture of nitrated compound and starting material. It wasdissolved in warm water and remaining solid was filtered (startingmaterial). Pure title compound (0.65 g, 25%) was obtained by extractingthe water with ethyl acetate, drying (MgSO₄) and concentrating. ¹H NMR(CD₃OD):□ 8.12 (dd, 1H), 8.00 (m, 1H), 7.58 (t, 1H).

Part B.1-[3-cyano-4-fluorophenyl]-3-trifluoromethyl-4-nitro-5-[4-(1-methylimidazol-2′-yl)aminocarbonyl]pyrazole.

To a solution of1-[3-cyano-4-fluorophenyl]-3-trifluoromethyl-4-nitropyrazole-5-carboxylate(0.76 g, 2.2 mmol) in 100 mL of methylene chloride was added oxalylchloride (0.29 mL, 3.3 mmol) and 2 drops of DMF. The reaction wasallowed to stir at ambient temperature for 3 h, at which time gasevolution had ceased. The reaction was concentrated in vacuo. Theresidue was taken up in 100 mL of methylene chloride and then there wasadded 4-dimethylaminopyridine (0.81 g, 6.6 mmol) and4-(1-methylimidazol-2′-yl) aniline (0.38 g, 2.2 mmol). The reaction wasallowed to stir at ambient temparature overnight. The reaction wasdiluted with ethyl acetate, washed with 10% aq HCl, sat'd aq NaHCO₃ andbrine, dried (MgSO₄) and concentrated. The residue was purified by flashchromatography to afford 0.45 g (41%) of the title compound. ¹H NMR(CD₃OD):□ 8.12 (dd, 1H), 8.03 (m, 1H), 7.70-7.50 (m, 5H), 7.13 (d, 1H),6.98 (d, 1H), 3.72 (s, 3H). LRMS (ES⁺): 500.1 (M+H)⁺.

Part C.1-[3-cyano-4-fluorophenyl]-3-trifluoromethyl-6-[4-(1-methylimidazol-2′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-[3-cyano-4-fluorophenyl]-3-trifluoromethyl-4-nitro-5-[4-(1-methylimidazol-2′-yl)aminocarbonyl]pyrazole(113 mg, 0.23 mmol) in 20 mL of methanol was added copper (I) chloride(0.27 g, 2.7 mmol) and potassium borohydride (0.17 g, 3.2 mmol). Thereaction was allowed to stir at ambient temperature for 2 h. Thereaction was diluted with ethyl acetate, washed with sat'd ammoniumchloride and brine, dried (MgSO₄) and concentrated. The residue wastaken up in 10 mL of 95% formic acid and stirred at 100° C. for 2 h. Thereaction was cooled and concentrated, diluted with ethyl acetate, washedwith saturated NaHCO₃ and brine, dried (MgSO₄) and concentrated toafford the title compound that was used without purification. LRMS(ES⁺): 480.2 (M+H)⁺.

Part D.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[4-(1-methylimidazol-2′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onetrifluoroacetic acid salt.

To a solution of1-[3-cyano-4-fluorophenyl)-3-trifluoromethyl-6-[4-(1-methylimidazol-2′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(53 mg, 0.11 mmol) in 5 mL of DMF and 1 mL of water was addedN-acetylhydroxylamine (0.02 g, 0.33 mmol) and potassium carbonate (0.06g, 0.44 mmol). The reaction was allowed to stir at ambient temperatureovernight. The reaction was diluted with ethyl acetate, washed withbrine, dried (MgSO₄) and concentrated. The residue was purified by prepHPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradient with0.5% TFA) and lyophilized to afford the title compound of Example 25 asa white solid. LRMS (ES⁺): 493.3 (M+H)⁺.

Example 261-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one

To a solution of1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-4-azidopyrazole-5-carboxylic acid(5.77 g, 17.44) in a 1:1 mixture of tetrahydrofuran and methylenechloride (200 mL) was added oxalyl chloride (1.90 mL, 21.81 mmol) and 1drop of N,N-dimethylformamide. The solution was allowed to stir atambient temperature for several hours. The volatiles were removed underreduced pressure and the residue dried under high vacuum for severalhours. The residue was then dissolved in 200 mL of methylene chloridefollowed by the addition of 4-dimethylamino pyridine (4.44 g, 36.35mmol) and[2′-tert-butyldimethyl-siloxymethyl-3-fluoro-[1,1′]-biphen-4-yl]amine(4.82 g, 14.54 mmol) and the solution allowed to stir at ambienttemperature overnight. The solution was filtered though a pad of silicagel and the volatiles were removed in vacuum. The residue was purifiedby column chromatography using 1:1 hexane/ethyl acetate to give thetitle compound as a white solid (7.51 g, 67%). LRMS (ESI): 643.2 (M−H)⁻.

Part B.1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-3-fluoro-[1,1]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

(1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-4-azido)-5-[(2′-tert-butyldimethylsiloxymethyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole(7.51 g, 11.64 mmol) was dissolved in 300 mL of ethanol followed by theaddition of stannous chloride dihydrate (5.52 g, 29.12 mmol) and thesolution was warmed gently for 2 minutes. The solution was pouredthrough a plug of silica gel and the volatiles removed. The crudeproduct was dissolved in 100 mL of 95% formic acid and refluxed for 1hr. The volatiles were removed under vacuum and the residue driedovernight. The product was then dissolved in 200 mL of ethanol andcooled in an ice/water bath followed by the addition of lithiumhydroxide (1.26 g, 3.3 mmol) in 30 mL of water and the reaction stirredat ambient temperature for 2 hours. The solution was diluted with ethylacetate and washed with brine. The organics were dried over magnesiumsulfate and the residue was purified by prep HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford the title compound of Example 26 as a white solid. LRMS (ESI):515.1 (M+H)⁺.

Example 271-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]1-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

To a solution of1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 26, Part B (0.20 g, 0.39 mmol) in 150 mL of methylenechloride was added phosphorous tribromide (0.074 mL, 0.77 mmol) and thereaction was stirred at ambient temperature overnight. The solution wasslowly quenched with water and the organics extracted with ethylacetate. The organics were dried over magnesium sulfate, filtered andthe volatiles were removed under reduced pressure. The crude benzylbromide (0.22 g, 0.39 mmol) was dissolved in 50 mL of acetonitrilefollowed by the addition of pyrrolidine (0.11 mL, 1.34 mmol) and stirredat ambient temperature overnight. The volatiles were removed underreduced pressure and the residue was purified by prep HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford the title compound of Example 27 as a white solid.LRMS (ESI): 568.2 (M+H)⁺.

Example 281-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[(2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole(0.60 g, 0.92 mmol) was dissolved in 200 mL of methanol followed by theaddition of 50 mL of a 28% ammonium hydroxide solution and allowed thereaction to stir overnight at ambient temperature. The reaction wasconcentrated and the residue was purified by prep HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford the title compound of Example 28 as a white solid.LRMS (ESI): 539.1 (M+H)⁺.

Example 291-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2-(3-(R)-hydroxy-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.85 g, 1.71 mmol) was dissolved in 150 mL of methylene chloridefollowed by the addition of phosphorous tribromide (0.32 mL, 3.42 mmol)and stirred at ambient temperature overnight. The solution was slowlyquenched with water and the organics extracted with ethyl acetate. Theorganics were dried over magnesium sulfate, filtered and the volatilesremoved under reduced pressure. The crude benzyl bromide (0.42 g, 0.75mmol) was dissolved in 50 mL of acetonitrile followed by the addition of3-(R)-pyrrolidinol hydrochloride (0.55 mL, 4.50 mmol) and stirred atambient temperature overnight. The volatiles were removed under reducedpressure and the residue was purified by prep HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford 0.2 g (17%) of the title compound as a white solid. LRMS(ESI): 566.3 (M+H)⁺.

Part B.1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2′-(3-(R)-hydroxy-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt.

1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-(3-(R)-hydroxy-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.120 g, 0.20 mmol) was dissolved in 200 mL of methanol followed by theaddition of 50 mL of a 28% ammonium hydroxide solution and allowed thereaction to stir overnight at ambient temperature. The reaction wasconcentrated and the residue was purified by prep HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford the title compound of Example 29 as a white solid.

LRMS (ESI): 537.2 (M+H)+

Example 301-[4-methoxyphenyl]-3-(N-formylaminomethyl)-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one

1-(4-methoxyphenyl]-3-cyano-4-amino-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole(0.30 g, 0.59 mmol) was dissolved in 100 mL of ethanol followed by theaddition of 5 mL of trifluoroacetic acid and a catalytic amount of 10%palladium on carbon (0.03 g) and the reaction was stirred overnight atambient temperature under a balloon of hydrogen gas. The solution wasfiltered through a plug of Celite® and the volatiles were removed togive the title product as a grey/white solid (0.30 g, 99%). LRMS (ESI);510.1 (M+H)⁺.

Part B.1-[4-methoxyphenyl]-3-(N-formylaminomethyl)-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

1-[4-Methoxyphenyl]-3-aminomethyl-4-amino-5-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl)pyrazole (0.30 g, 0.59 mmol) was refluxedfor 3 hours in 75 mL of 95% formic acid. The volatiles were removedunder vacuum and the residue was purified by prep HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford the title compound of Example 30 as a white solid.LRMS (ESI): 548.1 (M+H)⁺.

Example 311-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-[1,1′-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one

Part A. □-Cyano-.□-ethoxycarbonyl-[4-fluoro-3-cyano)phenyl hydrazineimine.

To a solution of 4-fluoro-3-cyanoaniline (11.78 g, 86.5 mmol) inconcentrated HCl (20.2 mL, 173.0 mmol) was added 131 mL of water and theentire reaction was cooled in an ice/water bath. Sodium nitrite (6.5 g,95.20 mmol) was dissolved in 20 mL of water and slowly added to thereaction mixture. After stirring for 30 minutes, the diazonium solutionwas poured into a solution of ethyl cyanoacetate (7.60 mL, 95.20 mmol)and sodium acetate trihydrate (25.91 g, 190.40 mmol) in a mixture of 21mL of methanol and 44 mL of water at 0° C. The reaction was stirred at0° C. for 20 minutes during which time a heavy yellow precipitate of thetitle compound formed. The product was isolated and dried by suctionfiltration to afford 8.9 g (39%) of bright yellow product.

Part B.3-Ethyl-5-methyl1-(4-fluoro-3-cyano)phenyl-4-aminopyrazole-3,5-dicarboxylate.

□-Cyano-.□-ethoxycarbonyl-[4-fluoro-3-cyano)phenyl]hydrazine imine (4.00g, 15.37 mmol), methyl bromoacetate, (1.85 mL, 19.98 mmol) and potassiumcarbonate (5.31 g, 38.43 mmol) were dissolved in N,N-dimethyl formamideand heated to 100° C. for several hours. The solution was diluted withethyl acetate and washed 2 times with brine. The organics were driedover MgSO₄, filtered through a pad of silica gel and the volatiles wereremoved. The title compound was purified by dissolving in hot diethylether and collecting the solids (2.82 g, 55%).

Part C.3-Ethyl-5-methyl1-(4-fluoro-3-cyano)phenyl-4-azidopyrazole-3,5-dicarboxylate.

3-Ethyl-5-methyl1-(4-fluoro-3-cyano)phenyl-4-aminopyrazole-3,5-dicarboxylate (2.82 g,8.48 mmol) was dissolved in TFA and cooled to 0° C. followed by theaddition of NaNO₂ (0.70 g, 10.18 mmol) and then the reaction was stirredat that temperature for 45 min. NaN₃ was dissolved in a minimal amountof water and added in portions to the TFA solution. The solution wasallowed to stir at 00 C for 45 min and added slowly to a saturatedsolution of NaHCO₃. The organics were dried over MgSO₄, filtered througha plug of silica gel and the volatiles were removed to give the titlecompound as a tan solid (0.13 g, 4.2%).

Part D.1-(4-fluoro-3-cyano)phenyl-3-(ethoxycarbonyl)-4-azidopyrazole-5-carboxylicacid.

3-Ethyl-5-methyl1-(4-fluoro-3-cyano)phenyl-4-azidopyrazole-3,5-dicarboxylate (0.40 g,1.11 mmol) was dissolved in a 1:1 mixture of 1,4-dioxane/water andcooled in an ice water bath. Lithium hydroxide (0.04 g, 1.67 mmol) waspredissolved in a minimal amount of water and added to the stirringsolution in one portion. The reaction was allowed to warm to ambienttemperature and the reaction was followed by thin layer chromatography.The solution was extracted with water, the aqueous layer acidified with10% hydrochloric acid and the product extracted with ethyl acetate toyield the title compound as a white solid (0.35 g, 92%) LRMS (ESI):687.2 (2M-H)⁻.1-(4-fluoro-3-cyano)phenyl-3-(ethoxycarbonyl)-4-azidopyrazole-5-carboxylicacid (0.35 g, 1.0 mmol) was dissolved in a 1:1 mixture oftetrahydrofuran and methylene chloride (200 mL) followed by the additionof oxalyl chloride (0.130 mL, 17.58 mmol) and 1 drop ofN,N-dimethylformamide. The solution was allowed to stir at ambienttemperature for several hours. The volatiles were removed under reducedpressure and the residue dried under high vacuum for several hours. Theresidue was then dissolved in 200 mL of methylene chloride followed bythe addition of N,N-dimethylaminopyridine (3.58 g, 29.31 mmol) and[2′-tert-butyldimethylsiloxymethyl-3-fluoro-[1,1′]-biphen-4-yl]amine(3.88 g, 11.72 mmol) and the solution allowed to stir at ambienttemperature overnight. The solution was filtered though a pad of silicagel and the volatiles were removed in vacuum. The residue was usedwithout further purification (0.55 g, 86%). LRMS (ESI):508.1(M-OSi(t-Bu)Me₂+H)⁺.

Part F.1-(4-fluoro-3-cyano)phenyl-3-(ethoxycarbonyl)-6-[2′-formylhydroxymethyl-[1,1′-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

(1-(4-fluoro-3-cyano)phenyl-3-(ethoxycarbonyl)-4-azido-5-[2′-tert-butyldimethylsiloxy)methyl-[1,1′]-biphen-4-yl]aminocarbonyl]pyrazole(0.55 g, 0.86 mmol) was dissolved in 100 mL of ethanol followed by theaddition of stannous chloride dihydrate (0.49 g, 2.57 mmol) and thesolution warmed gently for several minutes. The solution was thenfiltered through a pad of silica gel and the volatiles removed underreduced pressure. The residue was dissolved in 100 mL of 96% formic acidand refluxed for 2 hours. The volatiles were removed under reducedpressure and the residue dissolved in ethylacetate and the solutionfiltered through a pad of silica gel and the volatiles removed underreduced pressure. The title product was purified by columnchromatography using 1:1 hexane:ethylacetate and isolated as a whitesolid (0.40 g, 86%), LRMS (ESI): 560.1 (M+Na)⁺.

Part G.1-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

1-(4-fluoro-3-cyano)phenyl-3-(ethoxycarbonyl)-6-[2′-formylhydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-(4,3-d]-pyrimidin-7-one(0.40 g, 0.74 mmol) was dissolved in N,N-dimethylformamide followed bythe addition of acetohydroxamic acid (0.22 g, 2.97 mmol) and potassiumcarbonate (0.41 g, 2.97 mmol) and stirred overnight at ambienttemperature. Potassium carbonate in 10 mL of ethanol was added to thesolution and heated to 80° C. for 1 hour. The solution was diluted withwater and the product immediately precipitated out and was isolated byfiltration. The residue was purified by prep HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilizedto afford the title compound of Example 31 as a white solid. LRMS (ESI):523.1 (M+H)⁺.

Example 321-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

1-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-N-hydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.05 g, 0.08 mmol) was dissolved in 10 mL of methylene chloridefollowed by the addition of phosphorous tribromide (0.022 mL, 0.23 mmol)and stirred at ambient temperature overnight. The solution was slowlyquenched with water and the organics extracted with ethyl acetate. Theorganics were dried over magnesium sulfate, filtered and the volatilesremoved under reduced pressure. The crude benzyl bromide was dissolvedin 10 mL of acetonitrile followed by the addition of pyrrolidine (0.04mL, 0.47 mmol) and stirred at ambient temperature overnight. Thevolatiles were removed under reduced pressure and the residue waspurified by prep HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford the titlecompound of Example 32 as a white solid. LRMS (ESI): 576.3 (M+H)⁺.

Example 331-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

Part A. N-[4-bromophenyl]caprolactam

4-Bromoaniline (20.0 g, 11.62 mmol) and triethylamine (17.8 mL, 12.78mmol) were dissolved in 250 mL of methylene chloride. 6-Bromohexanoylchloride (19.6 mL, 12.78 mmol) was added dropwise via an additionfunnel. The reaction mixture was stirred under N₂ for ½ h after theaddition was completed. It was diluted with methylene chloride andwashed with water, 1N aqueous HCl, 1N aqueous NaOH, and brine. It wasthen dried over MgSO₄ and concentrated to a white solid (37.20 g).

A solution of the above solid in 100 mL of DMF was added dropwise atroom temperature to a mixture of NaH (5.00 g of 60% dispersion, 12.47mmol) in 150 mL of DMF. The reaction mixture was stirred at roomtemperature for 2 h under N₂. It was then poured into 500 mL of waterand extracted with EtOAc. The combined organic mixture was washed withbrine, dried over MgSO₄, and concentrated to colorless oil. The titlecompound was then purified by chromatography on silica gel eluted withmethylene chloride to give 24.5 g of white solid (78%). LRXS (ES⁺):268.0, 270.0 (M+H)⁺. ¹H NMR (CDCl₃): δ 7.49 (d, 2H), 7.12 (d, 2H), 3.73(m,2H), 2.69 (m, 2H), 1.82 (m, 6H).

Part B. N-[4-bromophenyl]-3-oxocaprolactam

N,N-Diisopropylamine (11.0 mL, 78.4 mmol) was dissolved in 20 mL of dryTHF and cooled at 0° C. n-BuLi (29.4 mL of 2.5 M solution in hexane) wasadded. The mixture was stirred at 0 CC under N₂ for 30 minutes and thencooled to −78° C. It was then cannulated to a solution ofN-[4-bromophenyl]caprolactam (6.57 g, 24.5 mmol) in 100 mL of THF at−78° C. The mixture was stirred at −78° C. under N₂ for 1 h, and methylmethanethiosulfonate (8.1 mL, 78.4 mmol) was added. The cooling bath wasremoved, the mixture was allowed to warm up to room temperature andstirred for 12 h. It was quenched with H₂O and the THF was removed invacuo. The residue was dissolved in EtOAc and washed with water andbrine. It was then dried over MgSO₄ and concentrated. Chromatography onsilica gel with 20% EtOAc in hexane gave 1.40 g ofN-[4-bromophenyl]-3-bis(thiomethoxy) caprolactam and 4.42 g ofN-[4-bromophenyl]-3-mono(thiomethoxy) caprolactam. TheN-[4-bromophenyl]-3-mono(thiomethoxy) caprolactam isolated wasresubjected to the above conditions, and a total of 6.38 g ofN-[4-bromophenyl]-3-bis(thiomethoxy) caprolactam was isolated. LRMS(AP⁺): 361.9, (M+H)⁺.

N-[4-bromophenyl]-3-bis(thiomethoxy) caprolactam from above wasdissolved in 100 mL of CH₃CN and 25 mL of H₂O was added. Ceric ammoniumnitrate (38.86 g, 70.89 mmol) was then added. After stirring for fiveminutes, water (300 mL) was added and the mixture was extracted withEtOAc. The combined organic mixture was washed with water and brine. Itwas dried over MgSO₄ and concentrated. The desired product was purifiedby chromatography on silica gel eluted with 30% EtOAc in hexane to give1.25 g of light yellow oil (18%). LRMS (AP⁺): 283.9, (M+H)⁺. ¹H NMR(CDCl₃): δ 7.56 (d, 2H), 7.22 (d, 2H), 3.77 (t, 2H), 2.67 (t, 2H), 2.09(m, 2H), 1.98 (m, 2H).

Part C.1-[4-methoxyphenyl]-3-trifluoromethyl-7-[4-bromophenyl]-4,5,6,7-tetrahydropyrazolo-13,4-c]-azepin-8-one

N-[4-bromophenyl]-3-oxocaprolactam (0.37 g, 1.13 mmol), morpholine (0.25mL, 2.81 mmol), and p-toluenesulfonic acid (catalytic amount) wererefluxed with 30 mL benzene using a Dean Stark apparatus under N₂ for 12h. The solvent was removed in vacuo and the residue was dried undervacuum to give1,5,6,7-tetrahydro-1-(4-bromophenyl]-3-(morpholin-4-yl)-2H-azepin-2-one.LRMS (AP⁺): 351.0, 353.0, (M+H)⁺.

4-Dimethylaminopyridine (0.13 g, 1.13 mmol) was dissolved in 5 mL ofmethylene chloride and cooled in an ice-bath. Trifluoroacetic anhydride(0.16 mL, 1.13 mmol) was added. The mixture was stirred at 0° C. for %h, and a solution of1,5,6,7-tetrahydro-1-[4-bromophenyl]-3-(morpholin-4-yl)-2H-azepin-2-onein 5 mL of methylene chloride was added. The ice-bath was removed, andthe reaction mixture was stirred at room temperature under N₂ for 12 h.The reaction mixture was diluted with methylene chloride and washed withwater and brine. After drying over MgSO₄, it was concentrated to give1,5,6,7-tetrahydro-1-[4-bromophenyl]-3-(morpholin-4-yl)-4-trifluoroacetyl-2H-azepin-2-oneas brown oil. LRMS (AP⁺): 446.0, 448.0, (M+H)⁺.

The brown oil above and p-methoxyphenylhydrazine hydrochloride (0.20 g,1.13 mmol) were refluxed with 50 mL of acetic acid under N₂ for 20 h.The solvent was removed, the residue was dissolved in EtOAc and washedwith water, Saturated NaHCO₃, and brine. It was dried over MgSO₄,concentrated, and chromatographed on silica gel with 15-20% EtOAc inhexane to give 0.24 g of the desired product (40%) and 0.17 g of theregioisomer (28%). LRMS (ES⁺): 528.0, (M+H)⁺. ¹H NMR (CDCl₃): δ 7.71 (d,2H), 7.39 (d, 2H), 7.06 (d, 2H), 6.92 (d, 2H), 3.89 (t, 2H), 3.82 (s,3H), 3.04 (t, 2H), 2.22 (m, 2H).

Part D.1-[4-methoxyphenyl]-3-trifluoromethyl-7-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-S-one.

1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-bromophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(0.12 g, 0.23 mmol), 2-(tert-butylaminosulfonyl)phenylboronic acid (63.0mg, 0.25 mmol), tetrabutylammonium bromide (4 mg, 5 mol %),tetrakis(triphenylphosphine)palladium(0) (13 mg, 5 mol %) were refluxedwith 20 mL of benzene under N₂ for 12 h. The reaction was cooled. It wasfiltered through Celite® and washed with EtOAc. The mixture was washedwith water and brine, dried over MgSO₄, concentrated, andchromatographed on silica gel with 15-30% EtOAc in hexane to give 26 mgof the desired product (18%) and 96 mg of the starting material. LRMS(ES⁺): 613.4, (M+H)⁺.

The product above was refluxed with 10 mL of trifluoroacetic acid for ½h. The solvent was removed. It was purified by prep HPLC (C18 reversephase column, eluted with a H₂O/CH₃CN gradient with 0.05% TFA) andlyophilized to afford 5.7 mg of the title compound of Example 33 as awhite powder (24%). LRMS (ES⁺): 557.3, (M+H)⁺. ¹H NMR (CDCl₃): δ 8.12(d, 1H), 7.59 (t, 1H), 7.51 (m, 3H), 7.38 (m, 4H), 7.29 (d, 1H), 6.82(d, 2H), 4.51 (s, 2H), 4.00 (t, 2H), 3.82 (s, 3H), 3.10 (t, 2H), 2.31(m, 2H).

Example 341-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2′-aminosulfonyl-3-fluoro-[1,1's-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

The title compound was prepared by the same procedures as shown forExample 1 using 4-bromo-2-fluoroaniline as starting material. LRMS(ES⁺): 575.2, (M+H)⁺. ¹HNMR (CDCl₃) δ 8.15(d, 1H), 7.57 (m, 2H), 7.39(t, 2H), 7.32 (d, 2H), 7.27 (d, 2H), 6.93 (d, 2H), 4.51 (s, 2H), 3.93(t,2H), 3.82 (s, 3H), 3.11 (t, 2H), 2.27 (m, 2H).

Example 351-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

Part A.1-[4-methoxyphenyl]-3-trifluoromethyl-7-[2′-formyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-bromophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-onefrom Part C of Example 33 (0.17 g, 0.32 mmol), 2-formylphenylboronicacid (97.0 mg, 0.64 mmol), potassium phosphate (273.0 mg, 1.28 mmol) andtetrakis(triphenylphosphine)palladium (0) (19 mg) were refluxed with 20mL of dioxane under N₂ for 12 h. It was filtered through Celite® andwashed with EtOAc. The mixture was washed with water and brine, driedover MgSO₄, concentrated, and chromatographed on silica gel with 10-15%EtOAc in hexane to give 0.10 g of the desired product (62%). LRMS (ES⁺):506.4, (M+H)⁺. ¹H NMR (CDCl₃): δ 10.02 (s, 1H), 8.02 (d, 1H), 7.64 (t,1H), 7.52 (t, 1H), 7.42 (m, 6H), 6.83 (d, 2H), 3.99(t, 2H), 3.82 (s,3H), 3.10 (t, 2H), 2.29 (m, 2H).

Part B.1-[4-methoxyphenyl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt.

The product from Part A was dissolved in 15 mL of MeOH. Pyrrolidine(0.049 mL, 0.59 mmol) and NaBH₄ (13 mg, 0.40 mmol) were added. Themixture was stirred at room temperature under N₂ for 12 h. It wasquenched with water, extracted with methylene chloride, dried overMgSO₄₁ concentrated, and purified by prep HPLC (C18 reverse phasecolumn, eluted with a H₂O/CH₃CN gradient with 0.05% TFA) and lyophilizedto afford 24 mg of the title compound of Example 35 as a TFA salt (18%).LRMS (ES⁺): 557.3, (M+H)⁺. ¹H NMR (CD₃OD): δ 7.66 (m, 1H), 7.35-7.56 (m,9H), 6.98 (d, 2H), 4.40 (s, 2H), 4.01 (t, 2H), 3.81 (s, 3H), 3.32 (m,2H), 3.08 (t, 2H), 2.80 (m, 2H), 2.29 (m, 2H), 1.88 (m, 4H).

Example 361-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

Part A.1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-7-[4-bromophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

N-[4-bromophenyl]-3-oxocaprolactam (1.31 g, 4.63 mmol), morpholine (1.60mL, 18.52 mmol), and p-toluenesulfonic acid (catalytic amount) wererefluxed with 50 mL benzene using a Dean Stark apparatus under N₂ for 12h. The solvent was then removed in vacuo and the residue was dried undervacuum to give1,5,6,7-tetrahydro-1-[4-bromophenyl]-3-(morpholin-4-yl)-2H-azepin-2-oneas a yellow solid. LRMS (AP⁺): 351.0, 353.0, (M+H)⁺.

4-Dimethylaminopyridine (0.68 g, 5.56 mmol) was dissolved in 20 mL ofmethylene chloride and cooled in an ice-bath. Trifluoroacetic anhydride(0.79 mL, 5.56 mmol) was added. The mixture was stirred at 0° C. for ½h, and a solution of the solid formed above in 20 mL of methylenechloride was added. The ice-bath was removed, and the reaction mixturewas stirred at room temperature under N₂ for 12 h. It was diluted withmethylene chloride and washed with water and brine. After dried overMgSO₄, it was concentrated to give1,5,6,7-tetrahydro-1-[4-bromophenyl]-3-(morpholin-4-yl)-4-trifluoroacetyl-2H-azepin-2-oneas brown oil. LRMS (AP³¹ ): 446.0, 448.0, (M+H)⁺.

The brown oil above and 3-cyano-4-fluorophenylhydrazine hydrochloride(1.31 g, 6.95 mmol) were refluxed with 100 mL of acetic acid under N₂for 20 h. The solvent was removed, the residue was dissolved in EtOAcand washed with water, saturated NaHCO₃, and brine. It was dried overMgSO₄, concentrated, and chromatographed on silica gel with 15-20% EtOAcin hexane to give 1.06 g of the desired product (46%). LRMS (ES⁺):493.1, (M+H)⁺. ¹H NMR (CDCl₃): 37.77 (m, 2H), 7.54 (d, 2H), 7.28 (m,3H), 7.15 (d, 2H), 3.91 (t, 2H), 3.10 (t, 2H), 2.28 (m, 2H).

Part B.1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-7-[2′-formyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one.

1-[3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-[4-bromophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(1.06 g, 2.15 mmol), 2-formylphenylboronic acid (0.65 g, 4.30 mmol),potassium phosphate (1.83 g, 8.60 mmol),tetrakis(triphenylphosphine)palladium (0) (124 mg) were refluxed with 80mL of dioxane under N₂ for 12 h. It was filtered through Celite® andwashed with EtOAc. The mixture was washed with water and brine, driedover MgSO₄, concentrated, and chromatographed on silica gel with 15-25%EtOAc in hexane to give 0.90 g of the desired product (81%). LRMS (ES⁺):519.3, (M+H)⁺. ¹H NMR (CDCl₃): δ 10.02 (s, 1H), 8.04 (d, 1H), 7.80 (m,2H), 7.68 (t, 1H), 7.54 (t, 1H), 7.43 (m, 4H), 7.30 (m, 1H), 4.02 (m,2H), 3.12 (t, 2H), 2.32 (m, 2H).

Part C.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one.

1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-7-[2′-formyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(0.90 g, 1.74 mmol) was dissolved in 20 mL of methanol and cooled at 0°C. NaBH₄ (76.0 mg, 2.00 mmol) was added. After stirring for ½ h at 0°C., it was quenched with water. The solvent was removed. The residue waspartitioned between methylene chloride and water. The aqueous layer wasextracted with methylene chloride. The combined organic solution waswashed with brine, dried over MgSO₄, concentrated to yellow foam. Thealcohol formed such was used in the next step without furtherpurification.

N-Acetylhydroxylamine (0.39 g, 5.22 mmol) was dissolved in 10 mL of DMF.Potassium carbonate (0.96 g, 6.96 mmol) was added, followed by 2 mL ofwater. After stirring for ½ h, a solution of the alcohol from above in 5mL of DMF was added. The reaction mixture was stirred at roomtemperature under N₂ for 12 h. Water was added, the precipitate wasfiltered and dried to give 0.90 g of the desired product (97%). LRMS(AP⁺): 534.2, (M+H)⁺. ¹H NMR (CDCl₃): δ 7.67 (m, 2H), 7.50 (m, 1H),7.42-7.20 (m, 8H), 4.52 (s, 2H), 3.97 (m, 2H), 3.10 (t, 2H), 2.30 (m,2H), 2.06 (bs, 1H).

Part D.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt.

1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(0.15 g, 0.28 mmol) was dissolved in 6 mL of dry methylene chloride.PBr₃ (0.037 mL, 0.39 mmol) was added and the mixture was stirred at roomtemperature under N₂ for 30 minute. The reaction mixture was quenchedwith water and extracted with methylene chloride. The methylene chlorideextract was washed with brine, dried over MgSO₄, and concentrated toyellow foam.

The foam was then dissolved in 10 mL of CH₃CN, and pyrrolidine (0.070mL, 0.84 mmol) was added. The mixture was stirred at room temperaturefor 12 h. It was concentrated, and purified by prep HPLC (C18 reversephase column, eluted with a H₂O/CH₃CN gradient with 0.05% TFA) andlyophilized to afford 0.11 of the title compound of Example 36 as a TFAsalt (56%). LRMS (ES⁺): 587.3, (M+H)⁺. ¹H NMR (CD₃OD): δ 7.96 (m, 1H),7.73-7.60 (m, 3H), 7.58-7.34 (m, 7H), 4.38 (s, 2H), 4.04 (t, 2H), 3.33(m, 2H), 3.14 (t, 2H), 2.78 (m, 2H), 2.32 (m, 2H), 1.86 (m, 4H).

Example 371-[3-Aminobenzisoxazol-51-yl]-3-trifluoromethyl-7-[2′-N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c3-azepin-8-one,trifluoroacetic acid salt

The title compound of Example 37 was prepared by the same methodsdescribed in Example 36. LRMS (ES⁺): 561.4, (M+H)⁺. ¹H NMR (CD₃OD): δ7.96 (d, 1H), 7.71 (dd, 1H), 7.63 (m, 1H), 7.55 (m, 2H), 7.50 (m, 2H),7.40 (m, 4H), 4.34 (s, 2H), 4.07 (t, 2H), 3.15 (t, 2H), 2.60 (s, 6H),2.34 (m, 2H).

Example 381-[3-Aminobenzisoxazol-51-yl]-3-trifluoromethyl-7-[2′-N-isopropylaminomethyl-1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

The title compound of Example 38 was prepared by the same methodsdescribed in Example 36. LRMS (ES⁺): 575.4, (M+H)⁺. ¹H NMR (CD₃OD): δ7.97 (s, 1H), 7.71 (m, 1H), 7.62 (m, 1H), 7.53-7.36 (m, 8H), 4.18 (s,2H), 4.07 (t, 2H), 3.20 (m,1H), 3.15 (t, 2H), 2.33 (t, 2H), 1.14 (d,6H).

Example 391-[3-Aminobenzisoxazol-51-yl]-3-trifluoromethyl-7-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c3-azepin-8-one,trifluoroacetic acid salt

The title compound of Example 39 was prepared by the same methodsdescribed in Example 36. LRMS (ES⁺): 603.4, (M+H)⁺. ¹H NMR (CD₃OD): δ7.98 (d, 1H), 7.70 (m, 2H), 7.58-7.37 (m, 8H), 4.58-4.30 (m, 3H), 4.08(t, 2H), 3.60-3.35 (m, 1H), 3.15 (t, 2H), 3.00-2.78 (m, 2H), 2.34 (m,2H), 2.20-1.79 (m, 2H).

Example 401-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

Part A. N-(4-Bromo-2-fluorophenyl)caprolactam

4-Bromo-2-fluoroaniline (11.80 g, 62.1 mmol) and triethylamine (9.00 mL,64.6 mmol) were dissolved in 200 mL of methylene chloride.6-Bromohexanoyl chloride (13.26 g, 62.1 mmol) was added dropwise via anaddition funnel. The reaction mixture was stirred under N₂ for M h afterthe addition was completed. It was diluted with methylene chloride andwashed with water, 1N aqueous HCl, 1N aqueous NaOH, and brine. It wasthe dried over MgSO₄ and concentrated to a white solid (21.75 g).

A solution of the above solid in 200 mL of DMF was added dropwise atroom temperature to a mixture of NaH (2.85 g of 60% dispersion, 71.3mmol) in 100 mL of DMF. The reaction mixture was stirred at roomtemperature for 2 h under N₂. It was then poured into 500 mL of waterand extracted with EtOAc. The combined organic mixture was washed withbrine, dried over MgSO₄, and concentrated to orange oil. The titlecompound was then purified by chromatography on silica gel eluted with10-50% EtOAc in hexane to give 16.27 g of orange oil (92%). LRMS (ES⁺):286.1, 288.1 (M+H)⁺. ¹H NMR (CDCl₃): δ 7.29 (m, 2H), 7.09 (t, 1H), 3.65(t, 2H), 2.71 (t, 2H), 1.82 (m, 6H).

Part B. N-(4-Bromo-2-fluorophenyl)-3,3-dichlorocaprolactam

N-[4-bromo-2-fluorophenyl]caprolactam (6.96 g, 24.33 mmol) andphosphorus pentachloride (15.20 g, 72.99 mmol) were added together with200 mL of benzene and refluxed under N₂ for 2 h. The reaction mixturewas cooled and quenched with water and saturated aqueous NaHCO₃. It wasdiluted with EtOAc and washed with water and brine. The organic mixturewas then dried over MgSO₄, concentrated, and chromatographed on silicagel eluted with 10% EtOAc in hexane to give 4.97 g of the desiredproduct (58%). LRMS (ES⁺): 355.9 (M+H)⁺, ¹H NMR (CDCl₃): δ 7.32 (m, 2H),7.10 (t, 1H), 3.84 (m, 2H), 2.75 (t, 2H), 2.10 (m, 2H), 1.82 (m, 2H).

Part C.1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-7-[4-bromo-2-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-13,4-c]-azepin-8-one

N-[4-bromo-2-fluorophenyl]-3,3-dichlorocaprolactam (0.49 g, 1.38 mmol)was refluxed with 10 mL of morpholine under N₂ for 1 h. The solvent wasthen removed in vacuo. Toluene was added and the solid was filtered off.The filtrate was concentrated and dried under vacuum to give1,5,6,7-tetrahydro-1-[4-bromo-2-fluorophenyl]-3-(morpholin-4-yl)-2H-azepin-2-oneas brown oil (0.55 g). LRMS (AP⁺): 369.0, 371.0, (M+H)⁺.

4-Dimethylaminopyridine (0.22 g, 1.79 mmol) was dissolved in 5 mL ofmethylene chloride and cooled in an ice-bath. Trifluoroacetic anhydride(0.0.42 mL, 2.98 mmol) was added. The mixture was stirred at 0° C. for %h, and a solution of1,5,6,7-tetrahydro-1-[4-bromo-2-fluorophenyl]-3-(morpholin-4-yl)-2H-azepin-2-onein 15 mL of methylene chloride was added. The ice-bath was removed, andthe reaction mixture was stirred at room temperature under N₂ for 12 h.It was diluted with methylene chloride and washed with water and brine.After drying over MgSO₄, it was concentrated to give1,5,6,7-tetrahydro-1-[4-bromo-2-fluorophenyl]-3-(morpholin-4-yl)-4-trifluoroacetyl-2H-azepin-2-oneas brown oil. LRMS (AP⁺): 465.0.0, 467.0, (M+H)⁺.

1,5,6,7-Tetrahydro-1-[4-bromo-2-fluorophenyl]-3-(morpholin-4-yl)-4-trifluoroacetyl-2H-azepin-2-oneformed above and 3-cyano-4-fluorophenylhydrazine hydrochloride (0.42 g,2.24 mmol) were refluxed with 25 mL of acetic acid under N₂ for 20 h.The solvent was removed, the residue was dissolved in EtOAc and washedwith water, saturated NaHCO₃, and brine. It was dried over MgSO₄,concentrated, and chromatographed on silica gel with 25% EtOAc in hexaneto give 0.15 g of the desired product (19%). LRMS (AP⁺): 511.0, 513.0,(M+H)⁺. ¹H NMR (CDCl₃): δ 7.76 (m, 2H), 7.36 (m, 2H), 7.28 (m,1H), 7.17(m, 1H), 3.85 (t, 2H), 3.12 (t, 2H), 2.26 (m, 2H).

Part D.1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-7-[2′-formyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

1-(3-Cyano-4-fluoro)phenyl-3-trifluoromethyl-7-[4-bromo-2-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(0.15 g, 0.29 mmol), 2-formylphenylboronic acid (88.0 mg, 0.58 mmol),potassium phosphate (0.25 g, 1.16 mmol),tetrakis(triphenylphosphine)palladium (0) (34 mg) were refluxed with 20mL of dioxane under N₂ for 12 h. It was filtered through Celite® andwashed with EtOAc. The mixture was washed with water and brine, driedover MgSO₄, concentrated, and chromatographed on silica gel with 25%EtOAc in hexane to give 93.0 mg of the desired product (60%). LRMS(AP⁺): 537.1, (M+H)⁺. ¹H NMR (CDCl₃): δ 10.02 (s, 1H), 8.04 (d, 1H),7.80 (m, 2H), 7.68 (t, 1H), 7.54 (t, 1H), 7.40-7.20 (m, 6H), 3.97 (m,2H), 3.15 (t, 2H), 2.33 (m, 2H).

Part B.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-hydroxymethyl-3-fluoro-1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

1-(3-Cyano-4-fluoro)phenyl-3-trifluoromethyl-7-[2′-formyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(93.0 mg, 0.17 mmol) was dissolved in 10 mL of THF and cooled at 0° C.NaBH₄ (17 mg, 0.45 mmol) was added. After stirred for ½ h at 0° C., itwas quenched with water and extracted with EtOAc. The combined organicsolution was washed with brine, dried over MgSO₄, concentrated. Thealcohol formed such was used in the next step without furtherpurification.

N-Acetylhydroxylamine (38 mg, 0.51 mmol) was dissolved in 2 mL of DMF.Potassium carbonate (94 mg, 0.68 mmol) was added, followed by 2 drops ofwater. After stirred for ½ h, a solution of the alcohol from above in 3mL of DMF was added. The reaction mixture was stirred at roomtemperature under N₂ for 12 h. Water was added, the milky mixture wasextracted with EtOAc. The combined organic solution was washed withbrine, dried over MgSO₄, concentrated and dried to give 89 mg of thedesired product (95%). LRMS (AP⁺): 552.2, (M+H)⁺. ¹H NMR (CDCl₃): δ 8.01(s, 1H), 7.76 (d, 1H), 7.63 (dd, 1H), 7.54 (dd, 1H), 7.47-7.20 (m, 6H),4.55 (s, 2H), 4.47 (s, 2H), 3.83 (t, 2H), 3.13 (t, 2H), 2.30 (m, 2H),1.68 (bs, 1H).

Part F.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt.

1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(89 mg, 0.16 mmol) was dissolved in 10 mL of dry methylene chloride.PBr₃ (0.021 mL, 0.22 mmol) was added and the mixture was stirred at roomtemperature under N₂ for 30 minute. The reaction mixture was quenchedwith water and extracted with methylene chloride. The methylene chlorideextract was washed with brine, dried over MgSO₄, and concentrated toyellow foam.

The foam was then dissolved in 10 mL of CH₃CN, and (R)-3-pyrrolidinol(0.050 mL, 0.60 mmol) was added. The mixture was stirred at roomtemperature for 12 h. It was concentrated, and purified by prep HPLC(C18 reverse phase column, eluted with a H₂O/CH₃CN gradient with 0.05%TFA) and lyophilized to afford 49 mg of the title compound of Example 40as a TFA salt (42%). LRMS (ES⁺): 621.3, (M+H)⁺. ¹H NMR (CD₃OD): δ 7.96(d, 1H), 7.64 (m, 2H), 7.58-7.36 (m, 5H), 7.25 (m, 2H), 4.58-4.30 (m,3H), 4.02 (t, 2H), 3.60-3.35 (m, 1H), 3.15 (t, 2H), 3.00-2.78 (m, 2H),2.34 (m, 2H), 2.20-1.79 (m, 2H).

Example 411-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

The title compound of Example 41 was prepared by the same methodsdescribed in Example 40. LRMS (ES⁺): 605.3, (M+H)⁺. ¹H NMR (CD₃OD): δ7.97 (d, 1H), 7.67 (m, 2H), 7.57 (m, 3H), 7.50 (d, 1H), 7.42 (m, 1H),7.27 (dd, 2H), 4.41 (s, 2H), 4.03 (t, 2H), 3.36 (m,1H), 3.15 (t, 2H),2.82 (m, 2H), 2.33 (m, 2H), 1.90 (m, 4H).

Example 421-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[2′-N-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

The title compound of Example 42 was prepared by the same methodsdescribed in Example 40. LRMS (ES⁺): 579.3, (M+H)⁺. ¹H NMR (CD₃OD): δ7.97 (d, 1H), 7.68 (dd, 1H), 7.62 (m, 1H), 7.57 (m, 3H), 7.47 (t, 1H),7.42 (m, 1H), 7.25 (dd, 2H), 4.34 (s, 2H), 4.04 (t, 2H), 3.15 (t, 2H),2.62 (6, 6H), 2.32 (m, 2H).

Example 431-[3-Aminobenzisoxazol-51-yl]-3-trifluoromethyl-7-[2′-N-isopropylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

The title compound of Example 43 was prepared by the same methodsdescribed in Example 40. LRMS (ES⁺): 593.3, (M+H)⁺. ¹H NMR (CD₃OD): δ7.97 (d, 1H), 7.66 (dd, 1H), 7.59 (m, 1H), 7.53 (m, 3H), 7.47 (d, 1H),7.40 (m, 1H), 7.28 (m, 2H), 4.18 (s, 2H), 4.02 (t, 2H), 3.24 (m,1H),3.15 (t, 2H), 2.32 (m, 2H), 1.16 (d, 6H).

Example 441-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-(2-dimethylaminomethylimidazol-1′-yl)-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2-fluoro-4-iodophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(prepared by the procedures described in Example 40) (0.22 g, 0.40mmol), 2-(N,N-dimethylaminomethyl)imidazole (61 mg, 0.48 mmol),potassium carbonate (61 mg, 0,44 mmol), CuI (12 mg), and1,10-phenanthroline (11 mg) were heated with 8 mL of DMSO at 130° C.under N₂ for 12 h. The reaction mixture was cooled and 14% aqueous NH₄OHwas added. It was extracted with EtOAc, washed with brine, dried overMgSO₄, concentrated, and chromatographed on silica gel eluted with 5%MeOH in CH₂Cl₂. Final purification by prep HPLC (C18 reverse phasecolumn, eluted with a H₂O/CH₃CN gradient with 0.05% TFA) afforded 53.2mg of the title compound of Example 44 as a TFA salt (20%). LRMS (ES⁺):543.3, (M+H)⁺. ¹H NMR (CD₃OD): δ 7.68 (t, 1H), 7.54-7.36 (m, 5H), 7.27(d, 1H), 6.98 (d, 2H), 4.42 (s, 2H), 3.87 (t, 2H), 3.80 (s, 3H), 3.08(t, 2H), 2.83 (s, 6H), 2.25 (m, 2H).

Example 451-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-(imidazol-1′-yl)-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c3-azepin-8-one,trifluoroacetic acid salt

The title compound of Example 45 was prepared by the same methodsdescribed in Example 44. LRMS (ES⁺): 485.4, (M+H)⁺. ¹H NMR (CD₃OD): δ9.50(s, 1H), 8.12 (s, 1H), 7.82-7.66 (m, 4H), 7.43 (d, 2H), 7.00 (d,2H), 3.97 (t, 2H), 3.82 (s, 3H), 3.10 (t, 2H), 2.28 (m, 2H).

Example 461-[2-Aminomethylphenyl]-3-trifluoromethyl-7-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt

Part A.1-[2-Trifluoroacetamidomethylphenyl]-3-trifluoromethyl-7-[4-bromophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

To a solution of 2-(trifluoroacetamidomethyl) aniline (0.64 g, 2.94mmol) in 5 mL of acetic acid at 0° C. was added 5 mL concentrated HCl,followed by sodium nitrite (220 mg, 3.19 mmol) in 5 mL of H₂O. Afterstirred at 0° C. for 2 h, stannous chloride dihydrate (1.53 g, 6.73mmol) in 3 mL of concentrated HCl and 3 mL of H₂O was slowly added.After stirring at 0° C. for 1 h, a solution of1,5,6,7-tetrahydro-1-[4-bromophenyl]-3-(morpholin-4-yl)-4-trifluoroacetyl-2H-azepin-2-one(prepared in Part C of Example 33) (0.57 g, 1.18 mmol) in 20 mL of MeOHwas added. The mixture was heated at 70° C. for 3 h. The solvent wasremoved. The residue was dissolved in EtOAc and washed with water,saturated NaHCO₃, and brine. It was dried over MgSO₄, concentrated, andchromatographed on silica gel with 10-30% EtOAc in hexane to give 0.13 gof the desired product (19%). LRMS (AP⁺): 575.1, (M+H)⁺.

Part B.1-[2-Trifluoroacetamidomethylphenyl]-3-trifluoromethyl-7-[2′-thiomethyl-1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

1-[2-Trifluoroacetamidomethylphenyl])-3-trifluoromethyl-7-[4-bromophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(0.132 g, 0.23 mmol), 2-thiomethylphenylboronic acid (79 mg, 0.46 mmol),potassium phosphate (0.19 g, 0.92 mmol),tetrakis(triphenylphosphine)palladium (0) (13 mg) were refluxed with 20mL of dioxane under N₂ for 12 h. It was filtered through Celite® andwashed with EtOAc. The mixture was washed with water and brine, driedover MgSO₄, concentrated, and chromatographed on silica gel with 25%EtOAc in hexane to give 80.0 mg of the desired product (56%). LRMS(AP⁺): 619.1, (M+H)⁺.

Part C.1-[2-Trifluoroacetamidomethylphenyl]-3-trifluoromethyl-7-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one

To a solution of1-[2-trifluoroacetamidomethylphenyl]-3-trifluoromethyl-7-[2′-thiomethyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(80 mg, 0.13 mmol) in 10 mL of CH₂Cl₂ was added MCPBA (111 mg, 0.33mmol) at 0° C. The mixture was allowed to warm up to room temperatureand stirred for 12 h. It was diluted with CH₂Cl₂ and washed withsaturated aqueous NaHCO₃ and brine. It was dried over MgSO₄,concentrated, chromatographed on silica gel eluted with 50% EtOAc inhexane to give 25 mg of white solid. LRMS (AP⁻): 649.1, (M−H)⁻.

Part D.1-[2-Aminomethylphenyl]-3-trifluoromethyl-7-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one,trifluoroacetic acid salt.

1-(2-Trifluoroacetamidomethylphenyl]-3-trifluoromethyl-7-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one(25 mg, 0.039 mmol) and potassium carbonate (11 mg) were stirred with 6mL of MeOH and a few drops of H₂O under N₂ for 12 h. It was concentratedand purified by prep HPLC (C18 reverse phase column, eluted with aH₂O/CH₃CN gradient with 0.05% TFA) afforded 5 mg of the title compoundof Example 46 as a TFA salt. LRMS (ES⁺): 555.3, (M+H)⁺.

Example 47 1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-79-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A. 1-[4-bromophenyl]-3-hydroxy-4-acetyl-5,6-dihydropyridin-2-one.

Levulinic acid (10 g, 86.1 mmol) in CH₂Cl₂ (100 mL) was cooled to 0° C.and oxalyl chloride (90.4 mmol, 11.48 g) and a few drops of DMF wereadded. The reaction was allowed to warm to ambient temperature andstirred 18 h. The reaction was evaporated and the residue dissolved inCH₂Cl₂(50 mL) and added dropwise to a solution of 4-bromoaniline (81.1mmol, 13.95 g), Et₃N (100 mmol, 10.12 g) and DMAP (81.1 mmol, 9.9 g) inCH₂Cl₂ (100 mL) at 0° C. The reaction was allowed to warm to ambienttemperature and stirred 18 h. The reaction was filtered, washed with 1NHCl (3×) and 1N NaOH (3×), dried (MgSO₄) and evaporated. There wasobtained 9.4 g of N-[4-bromophenyl]-4-oxopentamide. Crystallization fromEtOAc gave material with mp 156.2° C.

N-[4-bromophenyl]-4-oxopentamide (18.5 mmol, 5 g) was added dropwise toa suspension of LiAlH₄ (74 mmol, 2.8 g) in THF (50 mL). When theaddition was completed, the reaction mixture was heated at reflux for 1h. The reaction was cooled to ambient temperature and water (2.8 mL), 1NNaOH (2.8 mL) and water (8.4 mL) were carefully added sequentially tothe reaction mixture. Low resolution mass spectroscopy (LRMS), showedonly product, N-[4-bromophenyl]-4-hydroxypentylamine, (M+H)⁺:258.0/260.0 m/z.

This solution was cooled to 0° C., then 4-methylmorpholine (37 mmol,3.75 g) and ethyl oxalyl chloride (37 mmol, 5.1 g) were added. Thereaction was allowed to warm to ambient temperature and stirred 3 h.LRMS showed the major portion of the product mixture to be themono-acylation product [M+H)+358.0/360.0 m/z] and a small amount of thedi-acylation product [M+H)⁺: 458.0/460.0 m/z]. The reaction mixture wasevaporated, dissolved in EtOAc, and washed with 1N HCl (3×), 1N NaOH(2×), dried (MgSO₄) and evaporated. There was obtained 4.34 g ofmaterial.

The product mixture from above was dissolved in MeOH (100 mL), cooled to0° C. and a freshly prepared solution of NaOMe in MeOH (ca. 0.2 g of Nametal in 10 mL of MeOH) added. The reaction was stirred at 0° C. for 2 hwhereupon all of the diacylation product was consumed and the ethylester in the monoacylation product was transesterified to the methylester. The reaction was evaporated, dissolved in CHCl₃ and washed with1N HCl, dried (MgSO₄) and evaporated to give 3.9 g of methylN-[4-bromophenyl]-N-(4-hydroxypentyl)oxalyl amide; LRMS (M+H)⁺:344.0/346.0 m/z.

DMSO (74 mmol, 5.8 g) was added dropwise to a solution of oxalylchloride (34 mmol, 17 mL of a 2M solution in CH₂Cl₂) in CH₂Cl₂ (50 mL)at −63° C. (dry ice/AcCN bath). The reaction was maintained at −63° C.for 15 min then methyl N-[4-bromophenyl]-N-(4-hydroxypentyl)oxalyl amide(3.9 g, 11.3 mmol) in CH₂Cl₂ (50 mL) was added dropwise. After 3 h at−63° C., Et₃N (96.4 mmol, 9.75 g) was added and the cooling bathremoved. After the reaction warmed to ambient temperature and stirredfor 1 h, water was added (150 mL), the layers were separated, washedwith 1N HCl (2×) and brine, dried (MgSO₄) and evaporated. There wasobtained 3.4 g (9.8 mmol) of methylN-[4-bromophenyl]-N-(4-oxopentyl)oxalyl amide; LRMS (M+H)⁺342.0/344.0m/z.

Methyl N-[4-bromophenyl]-N-(4-oxopentyl)oxalyl amide (9.8 mmol, 3.4 g)was added to a solution of NaOMe in MeOH (from 0.53 g of Na metal (23 mgatom) in 20 mL of MeOH). This mixture was stirred at ambient temperaturefor 1 h, then 10 mL of 3N HCl was added. This suspension was dilutedfurther by the addition of more water (100 mL) and the product collectedby filtration and air-dried. There was obtained 1.72 g (5.6 mmol) of1-[4-bromophenyl]-3-hydroxy-4-acetyl-5,6-dihydropyridin-2-one; LRMS(M+H)⁻310.2/312.2 m/z.

Part B.1-[3-Cyano-4-fluorophenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one.

3-Cyano-4-fluoroaniline (3.7 mmol, 0.5 g) in conc. HCl (4 mL) was cooledto 0° C. and NaNO₂ (4.4 mmol, 0.3 g) in water (3 mL). This was stirredat 0° C. for 30 min, then acetic acid (1.3 mL) was added. SnCl₂·(H₂O)₂(8.5 mmol, 1.9 g) in 1:1 water:conc. HCl (3 mL) was added dropwise tothe cold solution and stirred for an additional 30 min. To this mixture1-[4-bromophenyl]-3-hydroxy-4-acetyl-5,6-dihydropyridin-2-one (3.9 mmol,1.2 g) was slurried in MeOH (20 mL) and added with the aid of additionalMeOH (6 mL). The suspension was heated at 50° C. for 3 h, then cooled at10° C. for 18 h. The product,1-[3-cyano-4-fluorophenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,was isolated by filtration. There was obtained 1.34 g (3.2 mmol) ofproduct; mp 237.6° C., LRMS (M+H)⁺: 425.2/427.1 m/z.

Part C.1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one.

1-[3-Cyano-4-fluorophenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one(1.34 g, 3.2 mmol), 2-formylphenylboronic acid (0.68 g, 4.5 mmol) andBu₄NBr (0.06 g) in C₆H₆ (50 mL) and 2N Na₂CO₃ (10 mL) was purged with astream of N₂ gas. Palladium tetrakis (triphenyl) phosphine (0.19 g, 5mol %) was added and the mixture heated at reflux for 18 h. To thecooled reaction mixture, brine and EtOAc was added and the layersseparated. The organic layer was dried (MgSO₄) and evaporated to give1.58 g (3.2 mmol) of1-[3-cyano-4-fluorophenyl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;LRMS (M+Na)⁺: 473.3 m/z.

1-[3-Cyano-4-fluorophenyl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one(3.4 g, 7.5 mmol) was cooled to 0° C. in MeOH (75 mL) and NaBH₄ (0.43 g,11.3 mmol) added. After 3 h, 1N HCl (50 mL) was added, the reaction wasevaporated and EtOAc added. The organic layer was washed with 1N HCl,dried (MgSO₄) and evaporated to give 2.48 g (5.5 mmol) of1-[3-cyano-4-fluorophenyl]-3-methyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one.

The product from above (2.48 g, 5.5 mmol), N-acetylhydroxylamine (1.24g, 16.4 mmol) and K₂CO₃ (4.54 g, 33 mmol) in DMF (75 mL) and water (7.5mL) were stirred at ambient temperature for 18 h. The solvent wasremoved by distillation and the residue applied to a flash silica gelcolumn (200 g) and eluted with a gradient of 2:1 to 1:1 hexane:EtOAc.There was obtained 1.65 g of1-[3-Aminobenzisoxazol-5-yl]-3-methyl-6-[2′-hydroxymethyl-[1,1′]-biphenyl-4-yl)-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;LRMS (M⁻) 464.0 m/z.

1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-hydroxymethyl-[1,1′]-biphenyl-4-yl)-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one(0.1 g, 0.22 mmol) in acetone (5 mL) and CH₂Cl₂ (20 mL) was stirred withactivated MnO₂ (0.3 g, 3.3 mmol). After 3 h the suspension was filteredthrough a pad of Celite® and evaporated to give 0.09 g of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one; LRMS (M+H)⁻: 464.2m/z.

Part D.1-(3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt.

To 0.09 g of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one(0.22 mmol) in 1:1 CHCl₃ THF (40 mL) was added pyrrolidine (0.064 g,0.88 mmol), acetic acid (0.44 mmol) and sodium triacetoxyborohydride(0.094 g, 0.44 mmol). After 18 h at ambient temperature more CHCl₃ wasadded (100 mL) and the organics washed with water, dried (MgSO₄) andevaporated. The residue (0.11 g) was purified by HPLC on a C₁₈ column byelution with a gradient of water (0.05% TFA, solvent A) and acetonitrile(0.05% TFA, solvent B). There was obtained 0.066 g of1-(3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-pyrrolidinylmethyl)-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt with a purity of >99%; mp 108.9° C., HRMS(C₃₁H₃₁O₂N₆)⁺: 519.2517 m/z.

Example 481-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(3-(S)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

This compound was prepared and purified by the same procedure outlinedin Example 47, Part D from a mixture of1-(3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[(3,4-c]-pyridin-7-oneand 3-(S)-hydroxypyrrolidine. There was obtained 0.047 g of the titlecompound of Example 48 with a purity >98%; mp 137.7° C.; HRMS(C₃₁H₃₁N₆O₃)⁺: 535.2452.

Example 491-[3-Aminobenzisoxazol-51-yl]-3-methyl-6-[2′-N-isopropylaminomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one trifluoroacetic acid salt

This compound was prepared and purified by the same procedure outlinedin Example 47, Part D from a mixture of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-oneand isopropylamine. There was obtained 0.065 g of the title compound ofExample 49 with a purity >95%; mp 71.5° C.; HRMS (C₃H₃₁N₆O₂)⁺: 507.2501.

Example 501-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

This compound was prepared and purified by the same A procedure outlinedin Example 47, Part D from a mixture of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-oneand a 2M THF solution of dimethylamine. There was obtained 0.040 g ofthe title compound of Example 50 with a purity >95%; mp 51.6° C.; HRMS(C₂₉H₂₉N₆O₂): 493.2355.

Example 511-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A.1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-thiomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one.

1-[3-Cyano-4-fluorophenyl)-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one(Example 47, Part B; 0.23 g, 0.54 mmol), 2-thiomethylphenylboronic acid(0.13 g, 0.76 mmol) and Bu₄NBr (0.011 g) in C₆H₆ (20 mL) and 2N Na₂CO₃(4 mL) was purged with a stream of N₂ gas. Palladium tetrakis(triphenyl)phosphine (0.032 g, 0.028 mmol) was added and the mixture heated atreflux for 18 h. To the cooled reaction mixture, brine and EtOAc wasadded and the layers separated. The organic layer was dried (MgSO₄) andevaporated then the residue was purified by silica gel chromatography(100 g of SiO₂, eluted with 1:1 hexane:EtOAc) to give 0.17 g (3.2 mmol)of1-[3-cyano-4-fluorophenyl]-3-methyl-6-[2′-thiomethyl)-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;LRMS (M+H)⁺: 469.0 m/z.

The product from above (0.17 g, 0.36 mmol), N-acetylhydroxylamine (0.08g, 1.09 mmol) and K₂CO₃ (0.30 g, 2.2 mmol) in DMF (5 mL) and water (0.5mL) were stirred at ambient temperature for 18 h. The reaction wasdiluted with EtOAc and washed with water (5×), dried (MgSO₄) andevaporated. The residue was applied to a flash silica gel column (50 g)and eluted with 1:1 hexane:EtOAc. There was obtained 0.09 g of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-thiomethyl)-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one.

A mixture of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-thiomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one(0.09 g, 0.19 mmol) and m-chloroperbenzoic acid (0.10 g, 0.56 mmol) inCH₂Cl₂ were stirred for 18 h. Saturated NaHCO3 was added and the layersseparated. The basic layer was extracted into CH₂Cl₂, then the organiclayers were combined, dried (MgSO₄) and evaporated. The residue waspurified by HPLC on a C₁₈ column by elution with a gradient of water(0.05% TFA, solvent A) and acetonitrile (0.05% TFA, solvent B). Therewas obtained 0.036 g of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-methylsulfonyl)-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt with a purity of >96%; mp 274.5° C., HRMS(C₂₇H₂₄O₄N₅S)⁺: 514.1527 m/z.

Example 521-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

The title compound was prepared by the same methods disclosed forExample 51. After HPLC purification there was obtained 0.24 g of1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt with a purity of >96%; mp 250.3° C., CHN forC₂₇H₂₂N₅O₄FS ·½ C₂F₃O₂H: Calcd. %C: 58.98, %H: 4.00, %N: 12.50, Found.%C: 59.02, %H: 4.17, %N: 12.56; HRMS (C₂₇H₂₃O₄N₅SF)⁻: 532.1471 m/z.

Examples 53 and 541-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt (Example 53) and cyclized byproduct (Example54).

Part A.1,5,6-Trihydro-1-[4-bromo-2-fluorophenyl]-3-(morpholin-4-yl)-pyridin-2-one.

To DMSO (16.6 mL) in CH₂Cl₂′ (200 mL) at −60° C. was added dropwisetrifluoroacetic anhydride (29.9 mL, 0.21 mol). This mixture was stirred15 min then 1-[4-bromo-2-fluorophenyl]-3-hydroxypiperidin-2-one (21 g,0.073 mol, prepared following the procedures in Marinelli et. al.Tetrahedron 1996, 11176) in CH₂Cl₂ (100 mL) was added dropwise. After 2h triethylamine (61.2 mL, 0.44 mol) was slowly added. The reaction wasstirred 1.5 h then poured into 1N HCl and the CH₂Cl₂ layer was separatedand concentrated. The residue was taken up in EtOAc and washed withwater, saturated aq NaHCO₃ and brine, dried (Na₂SO₄) and concentrated.The dione was placed in a Dean-Stark apparatus in benzene (200 mL) withmorpholine (13 mL) and p-toluenesulfonic acid (50 mg) and heated toreflux 18 h. The reaction was concentrated and purification bychromatography on silica with (2:1) hexanes/EtOAc as eluent afforded17.2 g (66%) of a pale yellow foam. ¹H NMR (CDCl₃): □ 7.41-7.12 (m, 3H),5.68 (t, j=4.7, 1H), 3.83 (4H, j=4.4 Hz, 4H), 3.71 (t, j=6.6 Hz, 2H),2.93 (t,j=4.8 Hz, 4H), 2.55 (dd, j=4.8, 6.6 Hz, 2H).

Part B.1-[2-Trifluoroacetamidomethylphenyl]-3-trifluoromethyl-6-[4-bromo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

To DMAP (0.5 g, 4.1 mmol) in CH₂Cl₂ (25 mL) at 0° C. was added TFAA(0.58 mL, 4.1 mmol). After 30 minutes1,5,6-trihydro-1-[4-bromophenyl]-3-[morpholin-4-yl]-pyridin-2-one (1.2g, 3.3 mmol) in CH₂Cl₂ (20 mL) was added. The reaction was stirred 24 hat rt. The solvent was removed and purification by chromatography onsilica with (2:1) hexanes/EtOAc as eluent afforded 0.79 g (52%) of ayellow solid. LRMS (ES−): 449-450.9 (M−H)⁻. The compound was heated toreflux for 3 h in THF (45 mL) containing 20% HCl (15 mL). The reactionwas cooled and extracted with diethyl ether, washed successively withNaHCO₃, brine and dried (Na₂SO₄). The trione intermediate was obtainedas a green-yellow foam (0.64 g, 90%). LRMS (ES⁺): 783-785 (2M+Na). Tothis product (0.62 g, 1.6 mmol) was added 2-hydrazinobenzyltrifluoroacetamide hydrochloride (1.0 g, 3.7 mmol) and acetic acid(20 mL) and the mixture was heated to reflux 24 h. The acetic acid wasremoved and the residue dissolved in EtOAc, washed successively withNaHCO₃, brine and dried (Na₂SO₄). Purification by chromatography onsilica with (4:1) hexanes/EtOAc as eluent afforded 0.3 g (32%) of thetitle compound. LRMS (ES−): 577-579.1 (M−H)⁻.

Part C.1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

1-[2-Trifluoroacetamidomethylphenyl]-3-trifluoromethyl-7-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(0.3 g, 0.052 mmol) was coupled with 2-thiomethylphenyl boronic acid(0.113 g, 0.06 mmol) via standard Suzuki coupling procedures with Pd°.Purification by chromatography on silica with (2:1) hexanes/EtOAc aseluent afforded 0.35 g of the desired thiomethyl intermediate. Thethiomethyl intermediate was dissolved in CH₂Cl₂, cooled to 0° C. andoxidized with m-chloroperbenzoic acid (0.39 g, 1.3 mmol). After stirringfor 2.5 h the reaction mixture was washed successively with sat'd sodiumbisulfate, brine and dried (MgSO₄). Purification by chromatography onsilica with (1:1) hexanes/EtOAc as eluent afforded 0.2 g of a foam. LRMS(ES−): 653.1 (M−H)⁻. The trifluoroacetamide group was removed by heatingto reflux the previous compound in a mixture of MeOH (10 mL), water (3mL), and K₂CO₃ (0.17 g, 1.2 mmol) for 3 h. The reaction was cooled,acidified with TFA, concentrated and purified via HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) to affordtwo products. First the desired ortho-benzyl amine (Example 53), 0.064mg (32% from sulfone) was recovered: Mass Spec m/z (ESI) (M+H)+559.1;HRMS (M+H)⁺ for C₂₇H₂₃F₄N₄O₃S₁: 599.1427; ¹H NMR (DMSO) □ 8.23 (s, 2H),8.12 (dd, j=1.1, 7.7 Hz, 1H) 7.82 (dt, j=1.5, 7.3 Hz, 1H), 7.74 (dt,j=1.5, 7.7 Hz, 1H), 7.67 (m, 2H), 7.55 (m, 2H), 7.53 (d, 1j=8 Hz, 1H),7.42 (m, 2H), 7.32 dd, j=1.8, 8 Hz, 1H), 4.18 (t, j=6.6 Hz, 2H), 3.88(q, j=5.8 Hz, 2H), 3.23 (t, j=6.2 Hz, 2H), 2.91 (s, 3H). A secondbyproduct the cyclic lactam (Example 54), 25 mg (12% from sulfone), wasrecovered: HRMS (M+H)⁺ for C₂₇H₂₃F₄N₄O₃S₁: 599.1429; ¹H NMR (DMSO) □8.21 (dd, j=1.1, 7.7 Hz, 1H), 7.86 (d, j=8 Hz, 1H), 7.65 (m, 2H), 7.56(m, 2H), 7.45 (dt, j=1.1, 7.3 Hz, 1H), 7.36 (m, 2H), 7.16 (dd, j=2.2,12.5 Hz, 1H), 7.06 (dd, j=1.5, 8.4 Hz, 1H), 6.81 (t, j=8.7 Hz, 1H), 4.25(d, j=5.9 Hz, 2H), 3.59 (t, j=6.2 Hz, 2H), 3.30 (m, 2H), 2.74 (s+m, 4H).

Example 551-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

The product from Example 53, Part B (0.33 g, 0.057 mmol) was coupledwith 2-(tert-butylaminosulfonyl)phenyl boronic acid (0.22 g, 0.08 mmol)via the Suzuki procedure. Purification by chromatography on silica with(2:1) hexanes/EtOAc as eluent afforded 0.23 g (56%) of a pale yellowsolid. LRMS (ES−): 710.2 (M−H)⁻. The protecting groups were removedsequentially by, first, stirring the previous compound in a mixture ofMeOH (30 mL), water (10 mL), and K₂CO₃ (0.086 g, 0.6 mmol) for 18 h. Thereaction was acidified with TFA and heated to reflux for 10 min. Thereaction was concentrated and purified by HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andfreeze-dried to afford 92 mg (44%) of the title compound of Example 55.HRMS (M+H)⁺ for C₂₆H₂₂F₄N₅O₃S₁: 560.1377. ¹H NMR (DMSO-d6) □ 8.21 (2H,s), 8.04 (dd, j=2.2, 5.1 Hz, 1H), 7.67 (m, 4H), 7.55 (m, 2H), 7.49 (t,j=8.1 Hz, 1H), 7.39 (s, 2H), 7.35 (m, 2H), 7.28 (dd, j=1.8, 8 Hz, 1H),4.16 (t, j=6.3 Hz, 2H), 3.89 (q, j=5.9 Hz, 2H), 3.23 (t, j=6.2 Hz, 2H).Analysis calc'd for C₂₆H₂₂F₄N₅O₃S₁ (TFA) (H₂O)₂: C: 47.39; H:3.69;N:9.87; found C:47.35; H:3.22; N:9.55.

Example 561-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

The title compound of Example 56 was prepared in a similar fashion tothat described for example 53. LRMS (ES⁺): 541.3 (M+H)⁺. ¹H NMR(DMSO-d6): 8.18 (bm, 2H), 8.09 (dd, 2H), 7.78-7.64 (cp, 6H), 7.54 (m,2H), 7.38 (m, 2H), 4.22 (t, 2H), 3.86 (m, 2H), 3.35 (bm, 1H), 3.20 (t,2H), 2.83 (s, 3H).

Example 571-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A.1-[2-Trifluoroacetamidomethylphenyl]-3-trifluoromethyl-6-[2′-formyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

The product from Example 53, Part B above (0.8 g, 1.4 mmol) was coupledwith 2-formylphenylboronic acid (0.311 g, 2.1 mmol) via standard Suzukimethodology. Purification by chromatography on silica with (2:1)hexanes/EtOAc as eluent afforded 0.5 g (59%) of the aldehydeintermediate. LRMS (ES−): 603.2 (M−H)⁻.

Part B.1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-13,4-c]-pyridin-7-onetrifluoroacetic acid salt.

The aldehyde from part A (0.16 g, 0.26 mmol) was hydrogenated at 40 psiin EtOH with 5% Pd/C (35 mg) and excess dimethylamine hydrochloride (50mg) for 6 h. The incomplete reaction was filtered through Celite®,concentrated and purification by chromatography on silica with 10%MeOH/CH₂Cl₂ as eluent afforded 77 mg (32%) of the trifluoroacetamide.The protecting group was removed in a mixture of MeOH (15 mL), water (8mL), and K₂CO₃ (34 mg, 0.2 mmol) for 18 h. The reaction was acidifiedwith TFA, concentrated, combined with another 60 mg of additional crudeproduct and purified via HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) to afford 94 mg (67%) of the titlecompound of Example 57. HRMS (M+H)⁺ for C₃₄H₂₉F₃N₂O 538.2234; ¹H NMR(DMSO-d6) .□ 8.26 (s, 2H), 7.73 (m, 1H), 7.67 (m, 2H), 7.58 (m, 5H),7.41 (dd, j=1.9, 11.4 Hz, 1H), 7.36 (m, 1H), 7.26 (dd, j=1.4, 8 Hz, 1H),4.31 (d, j=4.4 Hz, 2H), 4.17 (t, j=6.2 Hz, 2H), 3.88 (q, j=5.5 Hz, 2H),3.24 (t, j=6.6 Hz, 2H), 2.58 (s, 3H), 2.56 (s, 3H).

Example 581-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

The aldehyde from Example 57, Part A (0.225 g, 0.37 mmol) wasreductively aminated, with (S)-3-pyrrolidinol (100 mg, 1.1 mmol) andthen deprotected with K₂CO₃/MeOH/water, as in Example 57. Purificationby HPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradientwith 0.5% TFA) and freeze-drying afforded 80 mg (27%) of the titlecompound of Example 58 as a white solid: HRMS (M+H)⁻ for C₃₁H₃₀F₄N₅O₂:580.2313; ¹H NMR (DMSO-d6) □ 8.27 (m, 2H), 7.78 (m, 1H), 7.67 (m, 2H),7.55 (m, 5H), 7.40 (dd, j=1.8, 11.4 Hz, 1H), 7.33 (m, 1H), 7.27 (dd,j=1.4, 8 Hz, 1H), 4.46 (m, 3H), 4.16 w; (t, j=5.5 Hz, 2H), 3.87 (g,j=5.5 Hz, 2H), 3.50 m, 1H), 3.24 (t, j=6.6 Hz, 2H), 3.10-2.51 (m, 3H),2.10-1.60 (m, 3H). Analysis calc'd for C₃₁H₃₀F₄N₅O₂ (TFA)₂(H₂O)_(1.5);C: 50.37; H: 4.11; N: 8.39; found C: 50.05; H: 3.78; N:8.01.

Example 591-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A.1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-6-[4-bromo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

The trione intermediate from Example 53, Part B (4.1 g, 11 mmol) wascondensed with 3-cyano-4-fluorophenyl hydrazine (4.5 g, 13 mmol) inrefluxing AcOH (60 mL) for 18 h. The reaction was cooled, concentratedand the residue taken up in EtOAc. The organic layer was washedsuccessively with NaHCO₃, brine and dried (Na₂SO₄). Purification bychromatography on silica with (4:1) hexanes/EtOAc as eluent afforded3.68 g (67%) of the title compound as a foam. LRMS (ES−): 497-499(M−H)⁻.

Part B.1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-6-[2′-formyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-6-[4-bromo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(3.6 g, 7 mmol) was coupled with 2-formyl phenyl boronic acid (1.6 g,10.9 mmol) via Suzuki methodology. Purification by chromatography onsilica with (2:1) hexanes/EtOAc as eluent afforded 2.7 g (71.4%) of thetitle compound as a yellow foam. LRMS (ES−): 520.9 (M−H)⁻; 635(M−H+TFA).

Part C.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

To the aldehyde from Part B (3.68 g, 7.1 mmol) in MeOH (25 mL) at 0° C.was added NaBH₄ (0.31 g, 8 mmol) and the reaction was stirred 20 min.The MeOH was removed and the crude alcohol dissolved in CH₂Cl₂, washedwith water, brine and dried (MgSO₄). To N-acetylhydroxylamine (1.6 g, 21mmol) in DMF (15 mL) and water (1 mL) was added K₂CO₃ (3.9 g, 28 mmol).After 30 min. the above alcohol in DMF (15 mL) was added and thereaction was stirred 6 h. Water (75 mL) was added and the precipitatedproduct filtered off, dried in vacuo and used in the next step. LRMS(ES−): 536.1 (M−H)⁻.

Part D.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-dimethylaminomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt.

To a suspension of the alcohol from Part C (2.99 g, 5.6 mmol) in CH₂Cl₂(100 mL) was added PBr₃ (0.74 mL, 7.8 mmol). After 30 min. the reactionwas quenched with ice water. The aqueous layer was extracted withCH₂Cl₂, washed with brine and dried (Na₂SO₄) to afford 3.6 g. The crudebromide was used in the next step. To a portion of this intermediatebromide (0.5 g, 0.8 mmol) in CH₃CN (15 mL) was added excess 40% aqueousdimethylamine (1 mL, 9 mmol). After 24 h the reaction was concentratedand purification by HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and freeze-drying afforded 257 mg(45%) of the title compound of Example 59 as a white solid: HRMS(M+H)+for C₂₉H₂₅F₄N₆O₂: 565.1967; ¹H NMR (DMSO-d6)□ 9.50 (m, 2H), 8.11(d, j=2.2 Hz, 1H), 7.79 (dd, j=2.2, 8.8 Hz, 1H), 7.72 (m, 1H), 7.59 (m,4H), 7.41 (m, 2H), 7.26 (dd, j=1.4, 8 Hz, 1H), 4.32 (d, j=5.1 Hz, 2H),4.17 (t, j=6.2 Hz, 2H), 3.23 (t, j=6.6 Hz, 2H), 2.58 (s, 0.3H), 2.57 (s,3H).

Example 601-[3-Aminobenzisoxazol-51-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

To the intermediate bromide from Example 59, Part D (0.5 g, 0.8 mmol) inCH₃CN (15 mL) was added (R)-3-pyrrolidinol (0.22 g, 2.5 mmol). After 24h the reaction was concentrated and purification by HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andfreeze-drying afforded 283 mg (47%) of the title compound of Example 60as a white solid: HRMS (M+H)⁺ for C₃₁H₂₇F₄N₆O₃: 607.2075; ¹H NMR(DMSO-d6) □ 8.11 (d, j=1.8 Hz, 1H), 7.79 (dd, j=2.2, 8.8 Hz, 2H), 7.60(m, 4H), 7.40 (m, 2H), 7.27 (dd, j=1.4, 8 Hz, 1H), 4.48 (d, j=5.5 Hz,1H), 4.38 (m, 1H), 4.31 (m, 1H), 4.15 (t, j=6.2 Hz, 2H), 3.40 (m, 2H),3.22 (t, j=6.3 Hz, 2H), 3.15-2.70 (m, 4H), 2.20-1.70 (m, 3H).

Example 611-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

The title compound of Example 61 was prepared in a similar fashion tothat described above. HRMS (M+H)+ for C₃₁H₂₈F₃O₃N₆ 589.216 ¹H NMR(DMSO-d6): 8.11 (d, j=1.8 Hz, 1H), 8.81-7.65 (m, 2H), 7.58-7.45 (m, 5H),7.40-7.31 (m, 3H), 6.60 (b, 1H), 4.48 (d, j=5.5 Hz, 1H), 4.38 (m, 1H),4.31 (m, 1H), 4.15 (t, j=6.2 Hz, 2H), 3.40 (m, 2H), 3.22 (t, j=6.3 Hz,2H), 3.15-2.70 (m, 4H), 2.20-1.70 (m, 3H).

Example 62

1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-isopropylaminomethyl-3-fluoro-[1,1′-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

To the intermediate bromide from Example 59, Part D (0.62 g, 1.3 mmol)in CH₃CN (25 mL) was added isopropylamine (0.52 mL, 6.2 mmol). After 24h the reaction was concentrated and purification by HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andfreeze-drying afforded 308 mg (43%) of the title compound of Example 62as a white solid: HRMS (M+H)⁺ for C₃₀H₂₇F₄N₆O₂: 579.2158; ¹H NMR(DMSO-d6) □ 8.73 (m, 2H), 8.12 (d, j=1.8 Hz, 1H), 7.79 (dd, j=2.2, 8.8Hz, 1H), 7.72 (dd, j=1.8, 7.3 Hz, 1H), 7.63-7.49 (m, 4H), 7.43 (m+s,2H), 7.31 (dd, j=1.4, 8 Hz, 1H), 6.60 (m, 1H), 4.16 (t, j=6.2 Hz, 2H),4.11 (m, 2H), 3.26 (m, 1H), 3.20 (t, j=6.2 Hz, 2H), 1.14 (d, j=6.6 Hz,6H).

Example 631-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N-(2-methylimidazol-1-yl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

To the intermediate bromide from Example 59, Part D (0.2 g, 0.3 mmol) inCH₃CN (15 mL) was added 2-methylimidazole (0.11 mL, 1.3 mmol). After 24h the reaction was concentrated and purification by HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andfreeze-drying afforded 80 mg (34%) of the title compound of Example 63as a white solid: HRMS (M+H)⁺ for C₃₁H₂₄F₄N₇O₂: 602.1908; ¹H NMR(DMSO-d6) □ 8.12 d, j=1.8 Hz, 1H), 7.79 dd, j=2.1, 9.1 Hz, 1H), 7.60 (m,2H), 7.48 (dt, j=2.2, 4.7 Hz, 1H), 7.43-7.33 (m, 4H), 7.31 (d, j=1.8 Hz,1H), 7.28 (dd, j=1.8, 8.1 Hz, 1H), 7.12 (dd, j=8.2 Hz, 1H), 6.58 (m,2H), 5.35 (s, 2H), 4.15 (t, j=6.6 Hz, 2H), 3.22 (t, j=6.3 Hz, 2H), 2.31(s, 3H). HRMS (M+H)⁻ for C₃₁H₂₄F₄N₇O₂: 602.1908.

Example 641-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N-pyrrolidinomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

To the intermediate bromide from Example 59, Part D (0.27 g, 0.45 mmol)in CH₃CN (20 mL) was added pyrrolidine (0.17 g, 2.7 mmol). After 18 hthe reaction was concentrated and purification by HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andfreeze-drying afforded 113 mg (36%) of the title compound of Example 64as a white solid. HRMS (M+H)⁺ for C₃₁H₂₇F₄N₆O₂: 591.2141; ¹H NMR(DMSO-d6) □ 8.11 (d, j=2.2 Hz, 1H), 7.79 (dd, j=2.1, 9.1 Hz, 1H), 7.74m, 1H), 7.58 (m, 4H), 7.42 (m, 2H), 7.28 (dd, j=1.5, 8.1 Hz, 1H), 6.58(m, 2H), 4.39 (d, j=5.5 Hz, 2H), 4.16 (t, j=6.6 Hz, 2H), 3.35 m, 2H),3.22 (t, j=6.2 Hz, 2H), 2.82 (m, 2H), 1.81 (m, 4H).

Example 651-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-oximinomethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

1-[3-Cyano-4-fluorophenyl]-3-trifluoromethyl-6-[2′-4′formyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onefrom Example 59, Part B (2 g, 3.8 mmol) was reacted withN-acetylhydroxylamine (0.57 g, 7.6 mmol) and K₂CO₃ (1.6 g, 11.5 mmol) inDMF (15 mL). The reaction was stirred 18 h, then extracted with EtOAc,washed with water, brine and dried (MgSO₄). Purification through silicausing (2:1) hexanes/EtOAc as eluent afforded 1.6 g of a white solid. Aportion (100 mgs) of this solid was further purified by HPLC (C18reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA)and freeze-dried to afford 48 mg of the title compound of Example 65.HRMS (M+H)⁺ for C₂₇H₁₉F₄N₆O₃: 551.1436; Analysis calc'd for C₂₇H₁₈F₄N₆O₃(TFA)0.6: C:54.73; H:3.03; N:13.58; found C:54.71; H:3.10; N:13.55

Example 661-[4-Methoxyphenyl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A.1-[4-Methoxyphenyl]-3-trifluoromethyl-6-[4-bromo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

The trione intermediate from Example 53, Part B (0.49 g, 1.3 mmol) and4-methoxyphenylhydrazine hydrochloride (0.29 g, 1.7 mmol) were heated toreflux in a mixture of MeOH (30 mL) and AcOH (10 mL) for 18 h. Thereaction was cooled, concentrated and dissolved in EtOAc. The EtOAclayer was washed with NaHCO₃, brine, and dried (Na₂SO₄). Purificationthrough silica using (4:1) hexanes/EtOAc as eluent afforded 0.22 g (35%)of the title compound as a yellow oil. LRMS (ES+): 484-486 (M+H)⁺.

Part B.1-[4-Methoxyphenyl]-3-trifluoromethyl-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

1-[4-Methoxyphenyl]-3-trifluoromethyl-6-[4-bromo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(0.22 g, 0.45 mmol) was coupled with 2-formylphenyl boronic acid (0.102g, 0.6 mmol) via Suzuki procedure. After 18 h the reaction was filtered,concentrated, and the crude aldehyde used in next step. LRMS (ES−): 508(M−H)⁻. To the aldehyde in MeOH (10 mL) at 0° C. was added NaBH₄ (21 mg,0.5 mmol). After 2 h the reaction was quenched with water, extractedwith EtOAc and dried (MgSO₄). Purification by chromatography on silicawith (2:1) hexanes/EtOAc as eluent afforded 0.1 g (43%) of the titlecompound as a clear oil: ¹H NMR (CDCl₃) □ 7.54 (m, 1H), 7.51 (d, j=9.1Hz, 2H), 7.44-7.33 (m, 3H), 7.26-7.18 (m, 4H), 6.95 (d, j=9.2 Hz, 2H),4.59 (s, 2H), 4.13 (m, 2H), 3.82 (s, 3H), 3.23 (t, j=6.6 Hz, 2H).

Part C.1-[4-Methoxyphenyl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1′]-biphen-4-yl[-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt.

To a solution of1-[4-methoxyphenyl]-3-trifluoromethyl-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(0.1 g, 0.19 mmol) in CH₂Cl₂ (20 mL) was added PBr₃ (0.026 mL, 0.27mmol) and the reaction was stirred 2 h. After quenching with ice water,the bromide was extracted with CH₂Cl₂, washed with brine and dried(Na₂SO₄). Acetonitrile (20 mL) and R-(3)-pyrrolidinol (85 mg, 0.97 mmol)were added to the crude bromide and the reaction was stirred 72 h. Thereaction was concentrated and purification by HPLC (C18 reverse phasecolumn, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andfreeze-drying afforded 90 mg (66%) of the title compound of Example 66as a white solid: HRMS (M+H)⁺ for C₃₁H₂₉F₄N₄O₃: 581.2191; ¹H NMR(DMSO-d6) □ 7.78 (m,1H), 7.58(m, 3H), 7.53 (d, j=8.7 Hz, 2H), 7.41 (m,2H), 7.27 (dd, j=8.1, 1.9 Hz, 1H), 7.05 (d, j=9.2 Hz, 2H), 4.49 (d,j=5.5 Hz, 1H), 4.38 (m, 2H), 4.13 t, j=5.5 Hz, 2H), 3.81 (s, 3H),3.74-3.38 (m, 3H), 3.18 (t, j=6.2 Hz, 2H), 2.94 (m, 2H), 2.1-1.75 (m,2H).

Example 671-[3-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt

Part A.1-[3-Cyanophenyl]-3-trifluoromethyl-6-[4-bromo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

The trione intermediate from Example 53, Part B (1.8 g, 4.7 mmol) and3-cyanophenylhydrazine HCl (1 g, 6.1 mmol) were heated to reflux in MeOH(60 mL) and AcOH (15 mL) for 18 h. The solvents were removed andCH₂Cl₂/water added. The product was extracted with CH₂Cl₂, washed withbrine and dried (Na₂SO₄). Purification by chromatography on silica with(2:1) hexanes/EtOAc as eluent afforded 1.26 g (56%) of the titlecompound. LRMS (ES−): 476.9-478 (M−H)⁻.

Part B.1-[3-Cyanophenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one.

1-[3-Cyanophenyl]-3-trifluoromethyl-6-[4-bromo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(1.2 g, 2.5 mmol) was coupled with 2-thiomethylphenyl boronic acid (1 g,5.9 mmol) via Suzuki procedure. Purification by chromatography on silicawith (2:1) hexanes/EtOAc as eluent afforded 1 g of a yellow foam. Thethiomethyl intermediate was dissolved in CH₂Cl₂, cooled to 0° C. andoxidized with m-chloroperbenzoic acid (1.4 g, 4.6 mmol). After stirringfor 24 h the reaction mixture was washed successively with sat'd sodiumbisulfate, brine and dried (MgSO₄) to afford 0.73 g (52%) of the titlecompound as a yellow foam.

Part C.1-[3-Aminomethylphenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onetrifluoroacetic acid salt.

1-[3-Cyanophenyl]-3-trifluoromethyl-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(0.7 g, 1.3 mmol) was hydrogenated on the Parr at 45 psi in EtOH (30 mL)and TFA (2 mL) for 24 h. The reaction was filtered through Celite®,concentrated and purification by HPLC (C18 reverse phase column, elutionwith a H₂O/CH₃CN gradient with 0.5% TFA) and freeze-drying afforded 225mg (26%) of the title compound of Example 67 as a white solid: HRMS(M+H)³⁰ for C₂₇H₂₃F₄N₄O₃S: 559.1449; ¹H NMR (CDCl₃) □ 8.23 (s, 2H), 8.13(dd, j=1.1, 7.7 Hz), 7.79-7.67 (m, 3H), 7.66-7.65 (m, 1H), 7.58 (s,1H,+m, 2H), 7.44 (m, 2H), 7.33 (dd, j=1.8, 8 Hz, 1H), 4.17 (m, 4H), 3.18(t, j=6.2 Hz, 2H), 2.94 (s, 3H).

Example 681-[4-Methoxyphenyl]-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,bis-trifluoroacetic acid salt

Part A.1-(4-Methoxyphenyl)-3-(ethoxycarbonyl)-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-(4-Methoxyphenyl)-3-(ethoxycarbonyl)-4-azido-5-[(4-bromophenyl)aminocarbonyl]pyrazolefrom Example 11, Part A (2.00 g, 4:12 mmol) in ethanol was added tin(II) chloride dihydrate (3.7 g, 16.5 mmol) and the solution was stirredat reflux for 1 h. The solution was filtered through a pad of silica geland the silica rinsed with EtOAc. The volatiles were removed underreduced pressure and the residue was taken up in ethyl acetate, washedwith 1N sodium hydroxide and brine, dried (MgSO₄) and concentrated. Theresidue was refluxed for 2 hours in 10 mL of N,N-dimethylacetamidedimethyl acetal. The volatiles were removed under reduced pressure andthe solid residue was taken up in 20 mL of glacial acetic acid andstirred at reflux for 2 h. The reaction was cooled and concentrated, andthe residue was taken up in ethyl acetate, washed with saturated sodiumbicarbonate and brine, dried (MgSO₄) and concentrated to afford 1.5 g(75%) of the title compound as a solid. LRMS (ES+): 483.0/485.0 (M+H)+.

Part B.1-(4-Methoxyphenyl)-3-(hydroxymethyl)-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-(4-Methoxyphenyl)-3-(ethoxycarbonyl)-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.74 g, 1.53 mmol) in 20 mL of 1:1:1 methanol/THF/water was addedpotassium hydroxide (94 mg, 1.68 mmol) and the reaction was stirred atreflux for 2 h. The reaction was cooled to ambient temperature, dilutedwith water and extracted with hexanes/ethyl acetate (1:1). The aqueouslayer was acidified with 1N HCl and extracted with ethyl acetate. Thisextract was washed with brine, dried (MgSO₄) and concentrated to afford0.57 g (81%) of the carboxylic acid. This acid (0.57 g, 1.25 mmol) wastaken up in THF at 0° C. and then there was added N-methylmorpholine(0.19 mL, 1.38 mmol) and isobutyl chloroformate (0.18 mL, 1.38 mmol).After stirring for 20 min there was added sodium borohydride (95 mg, 2.5mmol) and the reaction was allowed to stir for 2 h. The reaction wasquenched with excess 1N HCl and diluted with ethyl acetate. The organicswere washed with brine, dried (MgSO₄) and concentrated. The residue waspurified by flash chromatography (elution with 2:1 hexanes/ethylacetate) to afford 0.40 g (73%) of the title compound.

Part C.1-(4-Methoxyphenyl)-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of1-(4-Methoxyphenyl)-3-(hydroxymethyl)-5-methyl-6-[(4-bromophenyl)1-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.19 g, 0.43 mmol) in 10 mL of methylene chloride was added phosphoroustribromide (0.23 g, 0.86 mmol) and the solution was allowed to stir atambient temperature for 3 h. The reaction was quenched with water,diluted with ethyl acetate, washed with brine, dried (MgSO₄) andconcentrated to afford a crude bromide, which was used withoutpurification. This residue (0.17 g, 0.34 mmol) was taken up in 5 mL ofDMF and then there was added imidazole (0.046 g, 0.67 mmol). Thereaction was allowed to stir at ambient temperature for 16 h. Thereaction was diluted with ethyl acetate, washed with brine, dried(MgSO₄) and concentrated to afford 160 mg (76%) of the title compound,which was sufficiently pure to be used without purification. LRMS (ES+):491.1/493.1 (M+H)+.

Part D.1-[4-Methoxyphenyl]-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(2′-formyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-(4,3-d]-pyrimidin-7-one.

To a solution of1-(4-Methoxyphenyl)-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.16 g, 0.33 mmol) in 10 mL of 1, ₄-dioxane was added2-formylphenylboronic acid (0.073 g, 0.49 mmol) and potassium phosphatetribasic (0.24 g, 1.15 mmol). This mixture was degassed with a stream ofnitrogen for 15 minutes. Following the purge,tetrakis(triphenylphosphine)palladium (0) (0.038 g) was added and thesolution was stirred at 100° C. for 4 h. The solution was cooled,diluted with EtOAc, washed twice with brine and the organics were driedover MgSO₄, filtered through a pad of silica gel and concentrated. Theresidue was purified by flash chromatography (elution with 2:1hexanes/ethyl acetate) to afford 0.08 g (47%) of the title compound.LRMS (ES+): 517.2 (M+H)+.

Part E.1-[4-Methoxyphenyl]-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,bis-trifluoroacetic acid salt.

To a solution of1-[4-Methoxyphenyl]-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(2′-formyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(80 mg, 0.15 mmol) in 5 mL of THF was added pyrrolidine (0.05 mL, 0.60mmol) and then sodium triacetoxyborohydride (64 mg, 0.3 mmol) and 2drops of glacial acetic acid. The reaction was allowed to stir atambient temperature for 3 h. The reaction was quenched with water anddiluted with ethyl acetate and saturated aqueous NaHCO₃. The organicswere washed with brine, dried (MgSO₄) and concentrated. The residue waspurified by prep HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford 28 mg (24%)of the title compound of Example 68. LRMS (ES+): 572.4 (M+H)⁺.

Examples 69 and 701-[4-Methoxyphenyl]-3-[(tetrazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt (Example 69) and1-[4-Methoxyphenyl]-3-[(tetrazol-2-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt (Example 70)

Part A.1-(4-Methoxyphenyl)-3-[(tetrazol-1-yl)methyl]-5-methyl-6-[(4-bromophenyl)-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-oneand1-(4-Methoxyphenyl)-3-[(tetrazol-2-yl)methyl]-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one

To a solution of1-(4-Methoxyphenyl)-3-(hydroxymethyl)-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.20 g, 0.45 mmol) in 10 mL of methylene chloride was added phosphoroustribromide (0.25 g, 0.90 mmol) and the solution was allowed to stir atambient temperature for 3 h. The reaction was quenched with water,diluted with ethyl acetate, washed with brine, dried (MgSO₄) andconcentrated to afford a crude bromide, which was used withoutpurification. This residue was taken up in 5 mL of DMF and then therewas added tetrazole (0.032 g, 0.45 mmol) and potassium carbonate (0.12g, 0.90 mmol). The reaction was allowed to stir at ambient temperaturefor 16 h. The reaction was diluted with ethyl acetate, washed with waterand brine, dried (MgSO₄) and concentrated to afford 180 mg (81%) of anapproximately 1:1 mixture of the title compounds, which was sufficientlypure to be used without purification.

Part B.1-[4-Methoxyphenyl]-3-[(tetrazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt (Example 69) and1-[4-Methoxyphenyl]-3-[(tetrazol-2-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt (Example 70).

Following the procedures described in Example 68, Parts D and E,1-(4-Methoxyphenyl)-3-[(tetrazol-1-yl)methyl]-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-oneand1-(4-Methoxyphenyl)-3-[(tetrazol-2-yl)methyl]-5-methyl-6-[(4-bromophenyl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onewere converted into the title compounds of Examples 69 and 70. The finalproducts were separated by prep HPLC (C18 reverse phase column, elutionwith a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford 11 mgof the title compound of Example 69 and 5 mg of the title compound ofExample 70. Example 69: LRMS (ES+): 574.3 (M+H)⁺. Example 70: LRMS(ES+): 574.3 (M+H)⁺.

Example 711-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

Part A. Ethyl[1-(3-cyano-4-fluoro)phenyl]-3-methyl-4-nitropyrazole-5-carboxylate.

Ethyl [1-(3-cyano-4-fluoro)phenyl]-3-methylpyrazole-5-carboxylate (32.3g, 118.21 mmol) was dissolved in 200 ml of trifluoroacetic acid followedby the addition of trifluoroacetic acid anhydride (116.9 ml, 827.48mmol) and the resulting solution was cooled to 0° C. Ammonium nitrate(18.92, 236.42 mmol) was added slowly in 4 portions and allowed to stirovernight with warming to ambient temperature. The solution wasneutralized with aq K₂CO₃ and the product was extracted with EtOAc. Theorganics were dried over MgSO₄, filtered through a plug of silica geland the volatiles removed in vacuo to afford 35.0 g (93%) of the titlecompound. LRMS (NH₃-DCI): 336.2 (M+NH₄)⁺.

Part B.[1-(3-cyano-4-fluoro)phenyl]-3-methyl-4-nitropyrazole-5-carboxylic acid.

Ethyl 1-(3-cyano-4-fluoro)phenyl-3-methyl-4-nitro-pyrazole-5-carboxylate(17.5 g, 54.99 mmol) was dissolved in 250 ml of methanol and cooled to0° C. followed by the addition of lithium hydroxide (1.31 g, 54.99 mmol)that was pre-dissolved in a minimum amount of water. The solution wasallowed to warm to RT. The reaction was followed by TLC and was completewithin 2 hrs. The product was extracted with water and acidified withdilute HCl. The product was extracted with EtOAc and dried over MgSO₄,and the volatiles were removed in vacuo to afford 12.5 g (78%) of thetitle compound. LRMS (ES−): 579.2 (2M−H)⁻.

Part C.[1-(3-cyano-4-fluoro)phenyl]-3-methyl-4-nitro-5-[(4-bromophenyl)aminocarbonyl]pyrazole.

[1-(3-Cyano-4-fluoro)phenyl]-3-methyl-4-nitropyrazole-5-carboxylic acid(11.5 g, 39.63 mmol) was dissolved in 300 ml of a 1:1 mixture ofCH₂Cl₂/THF followed by the addition of 5.18 ml (59.44 mmol) of oxalylchloride and 1 drop of DMF. This mixture was stirred at ambienttemperature for 2 h. The volatiles were removed and the crude acidchloride was dried under high vacuum for 1 h. The acid chloride was thendissolved in 200 ml of CH₂Cl₂ followed by the addition of 4-bromoaniline(6.13 g, 35.66 mmol) and DMAP (14.52 g, 118.89 mmol) and the resultingmixture was stirred at ambient temperature for 16 h. The solution wasfiltered through a plug of silica gel and the volatiles were removed.The crude product was dissolved in a minimal amount of EtOAc andtriturated with ethyl ether to afford 8.98 g (78%) of the titlecompound. LRMS (ES⁻): 414.1 (M−H)⁻.

Part D. [1-(3-cyano-4-fluoro)phenyl]-3-methyl-4-amino-5-[(4-bromophenyl)aminocarbonyl]pyrazole.

[1-(3-Cyano-4-fluoro)phenyl]-3-methyl-4-nitro-5-[(4-bromophenyl)aminocarbonyl]pyrazole(7.98 g, 17.96 mmol) was dissolved in 300 ml of methanol and cooled inan ice/water bath followed by the addition of CuCl (21.34 g, 215.59mmol) and the slow addition of NaBH₄ (13.56 g, 251.52 mmol) and stirredwith warming to ambient temperature over 2 h. The solution was pouredthrough a pad of silica gel and the volatiles removed to yield 7.11 g(95%) of the title compound that was sufficiently pure to be usedwithout purification.

Part E.[E-(3-cyano-4-fluoro)phenyl]-3,5-dimethyl-6-(4-bromophenyl)-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

[1-(3-Cyano-4-fluoro)phenyl]-3-methyl-4-amino-5-[(4-bromophenyl)aminocarbonyl]pyrazole(4.00 g, 9.65 mmol) was refluxed in a neat solution ofN,N-dimethylacetamide dimethyl acetal (50 ml) for 1 h. The volatileswere removed in vacuo and the crude intermediate was then refluxed in100 ml of glacial acetic acid for 1 h. The volatiles were removed invacuo and the residue was washed with ethyl ether and dried to afford2.2 g (53%) of the title compound.

Part F.1-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

Following the procedures described in Example 47, Part C,[1-(3-cyano-4-fluoro)phenyl]-3,5-dimethyl-6-(4-bromophenyl)-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onewas converted into the title compound.

Part G.1-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt.

1-(3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.80 g, 1.67 mmol) was dissolved in 100 ml of 1:1 CHCl₃/THF followed bythe addition of a 2.0M solution of dimethyl amine in methanol (3.3 ml,6.71 mmol) and 1 ml of HOAc. The solution was stirred at ambienttemperature for 10 min followed by the addition of sodiumtriacetoxyborohydride (0.71 g, 3.35 mmol) and the solution was stirredat ambient temperature overnight. After 18 h at ambient temperature moreCHCl₃ was added (100 mL) and the organics washed with water, dried(MgSO₄) and evaporated. The residue was purified by prep HPLC (C18reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA)and lyophilized to afford the title compound of Example 71 as a whitesolid. LRMS (ES⁺): 506.2 (M+H)⁺.

Example 721-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

Part A.[1-(3-cyano-4-fluoro)phenyl]-3-methyl-6-(4-bromophenyl)-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

[1-(3-Cyano-4-fluoro)phenyl]-3-methyl-4-amino-5-[(4-bromophenyl)aminocarbonyl]pyrazolefrom Example 71, Part D (2.48 g, 5.58 mmol) was refluxed in 100 ml of96% formic acid for 2 h. The volatiles were removed under vacuum, thecrude product was washed with a small amount of methanol and the productwas filtered and dried to afford 2.04 g (86%) of the title compound.

Part B.1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

Following the procedures described in Example 47, Part C,[1-(3-cyano-4-fluoro)phenyl]-3-methyl-6-(4-bromophenyl)-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onewas converted into the title compound.

Part G.1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt.

Following the procedure described in Example 71, Part G,1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onewas converted into the title compound of Example 72 as a white solid.LRMS (ES⁺): 492.2 (M+H)⁺.

Example 731-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-isopropylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

To a solution of1-[(3-aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(hydroxymethyl)-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,an intermediate from Example 72, Part B, (0.70 g, 1.57 mmol) in 200 mLof methylene chloride was added phosphorous tribromide (2.85 ml, 4.71mmol) and the solution was stirred at ambient temperature for 2 h. Thereaction was quenched by the addition of saturated K₂CO₃ solution andthe product extracted using EtOAc. The bromide was dried using MgSO₄,filtered and dried under vacuum. A portion of the crude bromide (0.14 g,0.26 mmol) was dissolved in 100 ml of CH₃CN followed by the addition ofisopropyl amine (0.22 mL, 2.5 mmol) and the resulting mixture wasstirred overnight. The volatiles were removed in vacuum and the productpurified by prep HPLC (C18 reverse phase column, elution with aH₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford the titlecompound of Example 73 as a white solid. LRMS (ES⁺): 506.2 (M+H)⁺.

Example 741-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

To a portion of the crude bromide from Example 73 (0.14 g, 0.26 mmol) in100 ml of CH₃CN was added (R)-3-hydroxypyrrolidine hydrochloride (0.32g, 2.6 mmol) and potassium carbonate (0.88 g, 6.40 mmol) and thereaction stirred at ambient temperature overnight. The volatiles wereremoved in vacuo and the product purified by prep HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford the title compound of Example 74 as a white solid.LRMS (ES⁺): 534.2 (M+H)⁺.

Example 751-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(4,5-dihydroimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

Part A. [N-(4-nitrophenyl)-N′-tert-butyloxycarbonyl]ethylene diamine.

To a solution of 4-fluoro-nitrobenzene (3.31 ml, 31.21 mmol) in 200 mLof THF was added 2-N-BOC ethylene diamine (5.0 g, 31.21 ml) and DMAP(5.72 g, 46.81 mmol) and the reaction was allowed to stir at ambienttemperature overnight. The volatiles were removed and the residue waspurified by flash column chromatography (elution with 1:1 hexane/EtOAc)to afford 4.17 g (47%) of the title compound.

Part B. [N-(4-aminophenyl)-N′-tert-butyloxycarbonyl]ethylene diamine.

[N-(4-nitrophenyl)-N′-tert-butyloxycarbonyl]ethylene diamine (4.17 g,14.82 mmol) was dissolved in 100 ml of MeOH followed by the addition of10% Pd/C (0.42 g) and placed on a Parr shaker under 55 psi of H₂ for 1h. The solution was filtered through a pad of Celite and the volatileswere removed to afford 3.35 g (90%) of the title compound. LRMS (ES⁺):252.4 (M+H)⁺.

Part C.[1-(3-cyano-4-fluoro)phenyl]-3-methyl-4-nitro-5-[[4-(2-N-(tert-butoxycarbonyl)aminoethylamino)phenyl]aminocarbonyl]pyrazole

[1-(3-Cyano-4-fluoro)phenyl)-3-methyl-4-nitropyrazole-5-carboxylic acidfrom Example 71, Part B (1.00 g, 3.44 mmol) was dissolved in 100 ml of1:1 CH₂Cl₂/THF followed by the addition of oxalyl chloride (0.45 ml,5.16 mmol) and 1 ml of DMF and the reaction was stirred at ambienttemperature for 2 h. The volatiles were removed under vacuum and thecrude acid chloride was dried under high vacuum for 1 hr. The residuewas then dissolved in 100 ml of CH₂Cl₂ followed by the addition[N-(4-aminophenyl)-N′-tert-butyloxycarbonyl]ethylene diamine (0.87 g,3.44 mmol) and DMAP (1.26 g, 10.33 mmol). The solution was allowed tostir overnight. The volatiles were removed under reduced pressure andthe residue was purified by flash column chromatography (eluting with1:1 hexane/EtOAc) to afford 1.15 g (64%) of the title compound. LRMS(ES⁺): 524.2 (M+H)⁺.

Part D.1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(4,5-dihydroimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt.

To a solution of the product of Part C (1.15 g, 2.19 mol) in 100 ml ofmethanol was added CuCl (2.60 g, 26.63 mmol) and KBH₄ (1.66 g, 30.75mmol). The reaction was stirred at rt for 2 h and the solution filteredthrough a pad of silica gel and the volatiles removed. The residue wasdissolved in 100 ml of 96% formic acid and refluxed for 6 h. Thevolatiles were removed and the residue washed with a small amount ofmethanol and filtered. The residue was dissolved in 50 ml of DMF and 2ml of H₂O and then there was added acetohydroxamic acid (0.14 g, 1.88mmol) and potassium carbonate (0.35 g, 2.51 mmol) the reaction wasstirred at rt overnight. Ethyl ether was added to the reaction and theproduct washed twice with brine and the product dried over MgSO₄ and thevolatiles removed under vacuum. The product was purified using prep HPLC(C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5%TFA) and lyophilized to afford the title compound of Example 75 as awhite solid. LRMS (ES⁺): 427.1 (M+H)⁺.

Example 761-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-(cyclopropylmethyl)aminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

To the crude bromide from Example 73 (0.03 g, 0.056 mmol) in 100 ml ofCH₃CN was added (aminomethyl)cyclopropane (0.005 mL, 0.056 mmol) and thereaction stirred at ambient temperature overnight. The volatiles wereremoved in vacuo and the product purified by prep HPLC (C18 reversephase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) andlyophilized to afford the title compound of Example 76 as a white solid.LRMS (ES⁺): 518.2 (M+H)⁺.

Example 771-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-(4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

Following the procedure described in Example 47, Part D,1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 72, Part B was converted into the title compound of Example77. LRMS (ES⁺): 518.2 (M+H)⁺.

Example 781-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(N-methyl-N-isopropyl)aminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

To a solution of1-[(3-aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 72, Part B (0.21 g, 0.44 mmol) in 100 ml of 1:1 CHCl₃/THFwas added N-methyl-N-isopropyl amine (0.18 ml, 1.76 mmol) and 1 ml ofHOAc. The solution was stirred at rt for 10 min followed by the additionof sodium triacetoxyborohydride (0.18 g, 0.88 mmol) and the solution wasstirred at rt overnight. The reaction was quenched with water, extractedwith ethyl acetate, and the extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified by prep HPLC(C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5%TFA) and lyophilized to afford the title compound of Example 78 as awhite solid. LRMS (ES⁺): 534.1 (M+H)⁺.

Example 791-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

To a solution of1-[(3-aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 71, Part F (0.30 g, 0.63 mmol) in 100 ml of 50 mL of THFwas added (R)-3-hydroxypyrrolidine (0.22 g, 2.52 mmol) and 1 ml of HOAc.The solution was stirred at rt for 10 min followed by the addition ofsodium triacetoxyborohydride (0.27 g, 1.26 mmol) and the solution wasstirred at rt overnight. The reaction was quenched with water, extractedwith ethyl acetate, and the extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified by prep HPLC(C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5%TFA) and lyophilized to afford the title compound of Example 79 as awhite solid. LRMS ES⁺): 548.2 (M+H)⁺.

Example 801-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

Part A.1-(3-Cyano-4-fluorophenyl)]-3-trifluoromethyl-4-nitro-pyrazole-5-carboxylicacid.

To a solution of ammonium nitrate (2.4 g, 0.03 mol) in 100 mL oftrifluoroacetic acid at 0° C. was added1-(4-fluoro-3-cyano)phenyl-3-trifluoromethyl-pyrazole-5-carboxylic acid(6.0 g, 0.02 mol). This mixture was stirred for 15 min to dissolve theacid and then there was added trifluoroacetic anhydride (14.1 mL, 0.10mol). The resulting mixture was allowed to stir with warming to ambienttemperature for 72 h. The reaction mixture was poured into water,extracted with ethyl acetate, washed with brine, dried (MgSO₄) andconcentrated to afford an approximately 2:1 mixture of product andstarting material, which were separated in the following way. Theresidue was stirred in 400 mL of water for several hours and the solidswere filtered and dried, yielding a mixture of product and recoveredstarting material. The filtrate was extracted with ethyl acetate, washedwith brine, dried (MgSO₄) and concentrated to afford 1.5 g (22%) of puretitle compound. The solids were resubjected to the purificationprocedure to afford an additional 2.0 g (29%) of the title compound. ¹HNMR (CD₃OD): □ 8.13 (dd, 1H), 8.02 (m, 1H), 7.58 (t, 1H).

Part B.[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one.

Following procedures described in Example 71, Part D, Example 72, Part Aand Example 47, Part C,[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-4-nitro-pyrazole-5-carboxylicacid was converted into the title compound.

Part C.[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-oneand[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one.

To a solution of[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-formyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one(0.59 g, 1.17 mmol) in 100 mL of THF was added sodium borohydride (0.04g, 1.17 mmol). The reaction was stirred at ambient temperature for 3 hand then was filtered through Celite, diluted with ethyl acetate, washedwith water and brine, dried (MgSO₄) and concentrated. Purification byflash chromatography (elution with 2:1 hexanes/ethyl acetate) afforded0.13 g of[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-oneand 0.12 g of the over reduction product,[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one.

Part D.1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt.

Following procedures described in Example 47, Part C and Example 71,Part G.[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onewas converted into the title compound of Example 80. LRMS (ES⁺): 546.3(M+H)⁺.

Example 811-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

Following procedures described in Example 47, Part C and Example 71,Part G, the over reduction product[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 80, Part C was converted into the title compound of Example81.

LRMS (ES⁺): 548.2 (M+H)⁺.

Example 821-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one,trifluoroacetic acid salt

Following procedures described in Example 47, Part C and Example 79, theover reduction product[1-(3-cyano-4-fluorophenyl)]-3-trifluoromethyl-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-onefrom Example 80, Part C was converted into the title compound of Example82. LRMS (ES⁻): 590.2 (M+H)⁺.

Example 831-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(S)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one,trifluoroacetic acid salt

Following the procedure described in Example 60, except that(S)-3-pyrrolidinol was used, the title compound of Example 83 wasprepared. Purification by HPLC and freeze-drying afforded 37 mg (15%):¹H NMR (DMSO-d6) □ 8.11 (d, j=1.9 Hz, 1H), 7.81 (d, j=9.9 Hz, 1H), 7.72(m, 1H), 7.58 (d, j=9.2 Hz, 2H), 7.54 (m, 2H), 7.51 (d, j=8.4 Hz, 2H),7.40 (d, j=8.4 Hz, 2H), 7.34 (m, 1H), 6.58 (brd s, 2H), 4.48 (d, j=5.5Hz, 1H), 4.37-4.29 (m, 2H), 4.23 (t, j=5.9, 2H), 3.50 (m, 2H), 3.18 (t,j=5.9 Hz, 2H), 2.95-2.85 (m, 2H,), 2.15-1.75 (m, 3H). LRMS (ES⁺): 589.2(M+H)⁺.

Example 841-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N-(pyrrolindinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one,trifluoroacetic acid salt

Following the procedure described in Example 60, except that pyrrolidinewas used, the title compound of Example 84 was prepared. Purification byHPLC and freeze-drying afforded 25 mg (11%): ¹H NMR (DMSO-d6).□ 8.11 (d,j=2.2 Hz, 1H), 7.81 (dd, j=2.2, 9.2 Hz, 1H), 7.73 (m, 1H), 7.58 (d,j=9.2 Hz, 2H), 7.54 (m, 2H), 7.51 (d, j=8.4 Hz, 2H), 7.41 (d, j=8.5 Hz,2H), 7.35 (m, 1H), 6.57 (brd s, 2H), 4.38 (d, t j=5.1 Hz, 2H), 4.23 (t,j=6.6, 2H), 3.34 (m, 2H), 3.19 (t, j=6.2 Hz, 2H), 2.81 (m, 2H,), 1.78(m, 4H) ppm. LRMS (ES⁺): 573.2 (M+H)⁺.

Example 851-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N-(morpholino)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one,trifluoroacetic acid salt

Following the procedure described in Example 60, except that morpholinewas used, the title compound of Example 85 was prepared. Purification byHPLC and freeze-drying afforded 110 mg (45.8%): ¹H NMR (DMSO-d6) □ 8.11(d, j=1.9 Hz, 1H), 7.81 (dd, j=2.2, 8.8 Hz, 1H), 7.76 (m, 1H), 7.58 (d,j=8.8 Hz, 2H), 7.54 (m, 1H), 7.51 (d, j=8.4 Hz, 2H), 7.40 (d, j=8.4 Hz,2H), 7.34 (m, 1H), 6.60 (brd s, 2H), 4.36 (brd s, 2H), 4.24 (t, j=6.6,2H), 3.77 (m, 2H), 3.59 (m, 2H), 3.21 (t, j=5.8 Hz, 2H), 3.17 (m, 2H,),2.78 (m, 2H) ppm. LRMS (ES⁺): 589.2 (M+H)⁺.

Example 861-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one,trifluoroacetic acid salt

Following the procedure described in Example 60, except thatdimethylamine in methanol was used, the title compound of Example 86 wasprepared. Purification by HPLC and freeze-drying afforded 180 mg (79%):¹H NMR (DMSO-d6) □ 9.55 (s, 1H), 8.11 (d, j=2.2 Hz, 1H), 7.81 (dd,j=2.2, 8.7 Hz, 1H), 7.72 (dd, j=3.7, 5.5 Hz, 1H), 7.57 (d, j=8.8 Hz,2H), 7.54 (dd, j=2.5, 5.8 Hz, 1H), 7.51 (d, j=8.8 Hz, 2H), 7.39 (d,j=8.5 Hz, 2H), 7.36 (dd, j=1.8, 5.4 Hz, 1H), 6.57 (s, 1H), 4.32 (d,j=4.8 Hz, 2H), 4.23 (t, j=6.6, 2H), 3.21 (t, j=6.2 Hz, 2H), 2.57 (s,3H,), 2.55 (s, 3H) ppm. LRMS (ES⁺): 547.2 (M+H)⁺.

Example 871-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[(3′-N-dimethylaminomethyl)-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound of Example 87 was prepared by the same methodsdescribed in Example 40. LRMS (ES⁺): 579.3, (M+H). ¹H NMR (CD₃OD) δ 7.98(t, 1H), 7.81 (d, 1H), 7.79 (s, 1H), 7.67 (t, 1H), 7.59 (m, 1H), 7.55(m, 2H), 7.51 (m, 2H), 7.47 (t, 1H), 4.39 (s, 2H), 4.01 (t, 2H), 3.15(t, 2H), 2.89 (s, 6H), 2.31 (m, 2H).

Example 881-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-7-[(3′-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example40. LRMS (ES³⁰ ): 605.3, (M+H)⁺. ¹H NMR (DMSO-d6) δ 8.10 (d, 1H), 7.89(s, 1H), 7.81 (d, 1H), 7.65 (m, 2H), 7.59 (m, 2H), 7.51 (m, 3H), 6.58(bs, 2H), 4.41 (d, 2H), 3.97 (t, 2H), 3.39 (m, 2H), 3.11 (m, 2H), 3.01(t, 2H), 2.19 (m, 2H), 2.03 (m, 2H), 1.85 (m, 2H).

Example 891-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(3′-N-pyrrolidinylmethyl)-[1,1′]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-B-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example35. LRMS (ES⁺): 579.3, (M+H)⁺. ¹H NMR (CDCl₃) δ 7.66 (s, 1H), 7.58 (d,1H), 7.48 (t, 1H), 7.45-7.31 (m, 6H), 6.93 (d, 2H), 4.27 (d, 2H), 4.10(bs, 2H), 3.91 (t, 2H), 3.80 (s, 3H), 3.72 (m, 2H), 3.10 (t, 2H), 2.90(m, 2H), 2.24 (m, 2H), 2.10 (m, 4H).

Example 901-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(3′-N-dimethylaminomethyl)-[1,1]′-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-9-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example35. LRMS (ES⁻): 553.3, (M+H)⁺. ¹H NMR (CDCl₃) δ 7.68 (s, 1H), 7.62 (d,1H), 7.53 (t, 1H), 7.48-7.31 (m, 6H), 6.93 (d, 2H), 4.22 (s, 2H), 3.90(m, 2H), 3.81 (s, 3H), 3.12 (t, 2H), 2.92 (bs, 2H), 2.81 (s, 62H), 2.25(m, 2H).

Example 911-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-benzimidazol-1′-yl-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example44. LRMS (ES⁺): 536.3, (M+H)⁺. ¹H NMR (CDCl₃) δ 8.87 (bs, 1H), 8.02 (d,1H), 7.59 (m, 4H), 7.45 (m, 4H), 6.95 (d, 2H), 3.87 (m, 2H), 3.82 (s,3H), 3.12 (t, 2H), A 2.30 (m, 2H).

Example 921-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-oneprepared by the same methods as shown in Example 40 (0.50 g, 0.90 mmol),N-bromosuccinimide (0.19 g, 1.08 mmol), and AIBN (9.0 mg) were refluxedwith 50 mL of CCl₄ under N₂ for 2 h. The reaction mixture was cooled andfiltered through Celite. The filtrate was concentrated to a brown solid.It was then dissolved in 20 mL of THF and 1, 8-diazabicyclo[5, 4,0]unden-7-ene (DBU, 0.14 mL) was added. The mixture was refluxed for 12h. The solvent was removed. It was dissolved in EtOAc and washed withwater and brine, dried over MgSO₄ and concentrated. Flash chromatographyon silica gel with 15% EtOAc in hexane gave 0.21 g of1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-6,7-dihydropyrazolo-[3,4-c]azepin-8-one.The title compound was then prepared from1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-6,7-dihydropyrazolo-[3,4-c]azepin-8-oneby the same methods shown in Example 40. LRMS (ES⁺): 603.2, (M+H)⁺. ¹HNMR (CDCl₃) 7.82 (d, 1H), 7.73 (m, 2H), 7.54-7.35 (m, 4H), 7.09 (dd,4H), 6.46 (m, 1H), 4.34 (s, 2H), 4.32 (d, 2H), 3.86 (bs, 2H), 3.59 (m,2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.85 (m, 2H).

Example 931-[3-Aminobenzisoxazo-5′-yl-3-trifluoromethyl-7-[(2′-N-dimethylaminomethyl)-3-fluoro-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example92. LRMS (ES⁺): 577.2, (M+H)⁺. ¹H NMR (CDCl₃) 7.82 (d, 1H), 7.73 (m,2H), 7.54-7.35 (m, 4H), 7.09 (dd, 4H), 6.46 (m, 1H), 4.33 (d, 2H), 4.29(s, 2H), 3.89 (bs, 2H), 2.58 (s, 6H).

Example 941-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N-(R)-3-hydroxypyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c-]azepin-8-one

The title compound was prepared by the same methods described in Example92. LRMS (ES⁺): 619.3, (M+H)⁺. ¹H NMR (CDCl₃) 7.78-7.59 (m, 4H),7.50-7.28 (m, 4H), 7.17-7.03 (m, 3H), 6.44 (m, 1H), 4.64 (s, 2H),4.42-4.15 (m, 3H), 3.63-3.25 (m, 2H), 2.95-2.50 (m, 2H), 1.97-1.62 (m,2H).

Example 951-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N-(R)-3-hydroxypyrrolidinylmethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example92. LRMS (ES⁺): 601.0, (M+H)⁺. ¹H NMR (CDCl₃) 7.79 (s, 1H), 7.68 (m,2H), 7.50-7.22 (m, 8H), 7.14 (d, 1H), 6.49 (m, 1H), 4.64 (s, 2H),4.42-4.15 (m, 3H), 3.63-3.25 (m, 2H), 2.95-2.50 (m, 2H), 1.97-1.62 (m,2H).

Example 961-[3-Aminobenzisoxazo-5′-yl]-3-trifluoromethyl-7-[(2′-N-dimethylaminomethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example92. LRMS (ES⁺): 559.2, (M+H)⁺. ¹H NMR (CDCl₃) 7.82 (d, 1H), 7.70 (m,2H), 7.53-7.38 (m, 5H), 7.28 (m, 2H), 7.14 (d, 1H), 6.50 (m, 1H), 4.39(d, 2H), 4.28 (s, 2H), 2.55 (s, 6H).

Example 971-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(2′-N-pyrrolidinylmethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example92. LRMS (ES⁺): 577.4, (M+H)⁺. ¹H NMR (CDCl₃) 7.77 (d, 1H), 7.55-7.35(m, 5H), 7.28 (m, 1H), 7.15-6.95 (m, 5H), 6.42 (m, 1H), 4.34 (s, 2H),4.28 (d, 2H), 3.85 (s, 3H), 3.60 (m, 2H), 2.58 (m, 2H), 2.03 (m, 2H),1.89 (m, 2H).

Example 981-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(2′-N,N-dimethylaminomethyl)-[1,1′]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-onetrifluoroacetic acid salt

The title compound was prepared by the same methods described in Example92. LRMS (ES⁺): 551.3, (M+H)⁺. ¹H NMR (CDCl₃) 7.77 (d, 1H), 7.55-7.35(m, 5H), 7.28 (m, 1H), 7.15-6.95 (m, 5H), 6.42 (m, 1H), 4.29 (d, 2H),4.27 (s, 2H), 3.84 (s, 3H), 2.60 (s, 6H).

Example 991[4-Methoxyphenyl]-3-trifluoromethyl-6-[(4-aminomethyl)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridin-7-onetrifluoroacetic acid salt

1[-Methoxyphenyl]-3-trifluoromethyl-6-[(4-carbomethyoxy)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridin-7-oneprepared by the same method as described in Park A of Example 66 (0.17g, 0.38 mmol) was dissolved in 20 mL of THF. Aqueous LiOH (0.5 mL of 1Msolution) was added. The mixture was stirred at room temperature underN₂ for 2 h. It was diluted with Et₂O and washed with water and brine. Itwas then dried over MgSO₄ and concentrated to give 0.16 g of the acid.It was then dissolve din 15 mL of THF and cooled at 0° C. under N₂. Toit was added Et₃N (0.057 mL) and isobutylchloroformate (0.056 mL). Thereaction mixture was stirred at 0° C. for 20 minutes. The precipitatewas filtered off and washed with 15 mL of THF. The filtrate wastransferred to another flask and to it was added NaBH₄ (28 mg) and a fewdrops of water. The mixture was stirred at 0° C. for 15 minute and thenat room temperature for 1 h. The reaction was quenched with aqueous HCland the solvent was removed. The residue was dissolved in EtOAc andwashed with water and brine. It was dried over MgSO₄, concentrated, andchromatographed with 1:1 EtOAc to hexane to give 70 mg of the benzylalcohol. LRMS (ES⁺): 418.1, (M+H)⁺.

The benzyl alcohol was dissolved in 7 mL of CH₂Cl₂ and PBr₃ (0.02 mL)was added. The mixture was stirred at room temperature for 30 minute. Itwas diluted with CH₂Cl₂ and washed with brine. After dried over MgSO₄,it was concentrated to a white solid. It was dissolved in 7 mL of DMFand NaN₃ (24 mg) was added. The mixture was stirred at 50° C. under N₂for 2.5 h. It was poured into water and extracted with EtOAc. The EtOAcextract was washed with brine, dried over MgSO₄, concentrated to givethe benzyl azide. The azide was dissolved in 10 mL of MeOH and refluxedwith SnCl₂.H₂O (0.31 mg) for 45 minutes. The solvent was removed. Theresidue was dissolved in EtOAc and saturated NaHCO₃ (4 mL) was added. Itwas filtered through Celite, concentrated, and purified by reverse phaseHPLC (C18 reverse phase column, eluted with a H₂O/CH₃CN gradient with0.05% TFA) and lyophilized to afford 40 mg the title compound as the TFAsalt (24%). LRMS (ES⁺): 417.2, (M+H)⁺. ¹H NMR (CDCl₃) δ 7.37 (d, 2H),7.12 (s, 4H), 6.84 (d, 2H), 4.01 (t, 2H), 3.67 (s, 3H), 3.58 (bs, 2H),3.11 (t, 2H).

Example 1001-[3-Aminomethylphenyl]-3-methyl-6-E[(2′-N-((3-(S)-hydroxy)pyrrolidinyl)methyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-onebis-trifluoroacetic acid salt

Part A.1-(3-Cyanophenyl)-3-methyl-6-(4-bromophenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one.

A mixture of1-(4-bromophenyl)-3-hydroxy-4-acetyl-5,6-dihydropyridin-2-one (3.2 mmol,1.0 g, Example 47, Part A) and 3-cyanophenylhydrazine (3.5 mmol, 0.60 g)in acetic acid (glacial, 40 mL) was heated at reflux for 3 h. Thereaction was evaporated, applied to a column of flash silica gel (ca.250 g) and eluted with gradient of 2:1 to 1:1 hexane:EtOAc. There wasobtained 0.4 g of the title compound,1-(3-cyanophenyl)-3-methyl-6-(4-bromophenyl)1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one.LRMS (ES⁺): 409/411 (M+H)⁺.

Part B.1-(3-Cyanophenyl)-3-methyl-6-[(2′-N-((3-(S)-hydroxy)pyrrolidinyl)methyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one.

1-(3-Cyanophenyl)-3-methyl-6-(4-bromophenyl)1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(0.49 mmol, 0.20 g), 2-formylphenylboronic acid (0.69 mmol, 0.10 g), andtetrabutylammonium bromide (0.024 mmol, 0.008 mmol) in benzene (12 mL)and 2N Na₂CO₃ (4 mL) was purged with N₂ gas for 15 min, then tetrakis(triphenylphosphine) palladium (0.031 mmol, 0.035 g) was added. Thismixture was heated at reflux for 18 h. To this mixture was added brineand it was then extracted with EtOAc. The extract was dried (MgSO₄) andevaporated. The residue was purified further by flash chromatographyusing a gradient of 5:1 to 1:1 hexane:EtOAc as an eluant. There wasobtained 0.12 g of the desired coupling product. LRMS (ES⁺): 431 (M−H)⁻.

This product (0.28 mmol, 0.12 g), 3 (S)-hydroxypyrrolidine (1.11 mmol,0.097 g), acetic acid (glacial, 0.03 g) and sodium triacetoxyborohydride(0.56 mmol, 0.12 g) in CHCl₃ (5 mL) was stirred at ambient temperaturefor 18 h. The reaction was evaporated, dissolved in CH₂Cl₂, washed withwater, dried (MgSO₄) and evaporated. There was obtained 0.13 g of thetitle compound. LRMS (ES⁺): 504 (M+H)⁺.

Part C.1-(3-Methylaminophenyl)-3-methyl-6-[(2′-N-((3-(S)-hydroxy)pyrrolidinyl)methyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-onebis-trifluoroacetic acid salt.

1-(3-Cyanophenyl)-3-methyl-6-[(2′-N-((3-(S)-hydroxy)pyrrolidinyl)methyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(0.26 mmol, 0.13 g) in MeOH (20 mL) with TFA (1 mL) was shaken under anatmosphere of H2 gas (50 psi) in the presence of 10% Pd-C catalyst (50mg) for 18 h. The reaction was purged with N2 gas, filtered through apad of Celite then evaporated. The residue was purified by HPLC on a Cl₈column by elution with a gradient of water (0.05% TFA, solvent A) andacetonitrile (0.05% TFA, solvent B). There was obtained 0.072 g of1-[3-aminomethylphenyl]-3-methyl-6-[(2′-N-((3-(S)hydroxy)pyrrolidinyl)methyl-[1,1′]-biphenyl-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-onebis-trifluoroacetic acid salt with a purity of >90%; mp 79.2° C.,

HRMS (C₃₁H₃₄O₂N₅)⁺: 508.2773 m/z.

Example 1011-[3-Aminomethylphenyl]-3-methyl-6-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

Part A.1-(3-cyanophenyl)-3-methyl-6-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one.

1-(3-Cyanophenyl)-3-methyl-6-(4-bromophenyl)1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(Example 100, Part A; 0.17 g, 0.42 mmol), 2-thiomethylphenylboronic acid(0.098 g, 0.58 mmol) and Bu₄NBr (0.008 g) in C₆H₆ (20 mL) and 2N Na₂CO₃(4 mL) was purged with a stream of N₂ gas. Palladium tetrakis(triphenyl) phosphine (0.02 g, 0.02 mmol) was added and the mixtureheated at reflux for 18 h. To the cooled reaction mixture, brine andEtOAc was added and the layers separated. The organic layer was dried(MgSO₄) and evaporated then the residue was purified by silica gelchromatography (100 g of SiO₂, eluted with 1:1 hexane:EtOAc) to give0.12 g (3.2 mmol) of1-(3-cyanophenyl)-3-methyl-6-[(21-thiomethyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one.LRMS (ES⁺): 451 (M+H)⁺.

A mixture of this product (0.12 g, 0.27 mmol) and m-chloroperbenzoicacid (0.14 g, 0.81 mmol) in CH2Cl12 were stirred for 18 h. SaturatedNaHCO3 was added and the layers separated. The basic layer was extractedinto CH2Cl12, then the organic layers were combined, dried (MgSO4) andevaporated to yield 0.14 g of the title compound. LRMS (ES⁺): 505(M+Na)⁺.

Part B.1-[3-Aminomethylphenyl]-3-methyl-6-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt.

The product from above was treated as in Example 100, Part C and theresidue was purified by HPLC on a C₁₈ column by elution with a gradientof water (0.05% TFA, solvent A) and acetonitrile (0.05% TFA, solvent B).There was obtained 0.066 g of the title compound of Example 101,1-[3-aminomethylphenyl]-3-methyl-6-[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt with a purity of >94%. mp 131° C., HRMS(C₂₇H₂₇O₃N₄S)⁺: 487.1819 m/z.

Example 102 1-[3-Aminobenzisoxazol-51-yl]-3-methyl-6-[(3-fluoro-2′-N-(3(S)-hydroxy)pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

This compound was prepared and purified by the same procedure outlinedin Example 47, Part D from a mixture of1-[(3-aminobenzisoxazol-5′-yl]-3-methyl-6-[(3-fluoro-2′-formyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-oneand 3 (S)-hydroxypyrrolidine. There was obtained 0.030 g of the titleproduct with a purity >98%. mp 207.7° C.; HRMS (C₃₁H₃₀N₆O₃F)⁺: 553.2377m/z.

Example 1031-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[(3-fluoro-2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one, trifluoroacetic acid salt

This compound was prepared and purified by the same procedure outlinedin Example 47, Part D from a mixture of1-[(3-aminobenzisoxazol-51-yl]-3-methyl-6-[(3-fluoro-2′-formyl-[1,1′]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-oneand pyrrolidine. There was obtained 0.029 g of the title product with apurity >97%. HRMS (C₃₁H₃₀N₆O₂F)⁺: 537.2421 m/z.

Example 1041-[1-Aminoisoquinolin-7′-yl]-3-trifluoromethyl-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onebis-trifluoroacetic acid salt

Part A.1-(Isoquinolin-7′-yl)-3-trifluoromethyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

1, 5, 6-Trihydro-1-(4-bromophenyl)-4-trifluoroacetyl-pyridin-2,3-dione(0.84 g, 1.87 mmol) and 7-hydrazinoisoquinoline (tin salt from SnCl₂reduction of diazonium salt) (0.72 g, 1.87 mmol) were heated to refluxin acetic acid (30 ml) for 4 h. The solvents were removed and ethylacetate/sodium bicarbonate (sat) was added. The product was extractedwith ethyl acetate, washed with brine and dried on sodium sulfate.Purification by chromatography on silica with (1:1) hexane/ethyl acetateas eluant afforded 0.60 g (64%) of the title compound. LRMS (ES+):505/507.0 (Br pattern) (M+H)⁺.

Part B.1-(1-Aminoisoquinolin-7′-yl)-3-trifluoromethyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridine-7-one

1-(Isoquinolin-7′-yl)-3-trifluoromethyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one(0.50 g, 1 mmol) was mixed with MCPBA (65%) (0.45 g, 1.2 mmol) inmethylene chloride. The mixture was stirred at RT overnight. Thesolvents were removed and ethyl acetate/sodium bicarbonate (sat) added.Organic layer was separated and washed with brine and dried on sodiumsulfate. Filtered and concentrated to give isoquinoline N-oxide (0.51 g,98%). LRMS (ES+): 521.2/523 (Br pattern) (M+H)⁺. The N-oxide was mixedwith p-TsCl (229 mg, 1.2 mmol) in pyridine (10 ml). The mixture wasstirred at RT overnight. Pyridine was removed under reduced pressure andethanolamine (8 ml) was added. The resulting mixture was stirred at RT 1h. Cold water was added and product was extracted with ethyl acetate,washed with brine and dried over sodium sulfate. Purification bychromatography on silica with (2:3) hexane/ethyl acetate as eluentafforded 0.26 g (50%) of the title compound. LRMS (ES+): 520.2/522.2 (Brpattern) (M+H)⁺.

Part C.1-[1-Aminoisoquinolin-7′-yl]-3-trifluoromethyl-6-[4-(2-methylimidazol-1′]-yl)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onebio-trifluoroacetic acid salt.

1-(1-aminoisoquinolin-7′-yl)-3-trifluoromethyl-6-[4-bromophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridine-7-one(0.25 g, 0.48 mmol) was mixed with 2-methylimidazole (59 mg, 0.72 mmol),potassium carbonate (133 mg, 0.96 mmol) and CuI (14 mg, 0.072) in DMSO.The mixture was degassed under argon for 15 min. The mixture was stirredat 125° C. for 10 h. The mixture was cooled to RT and partitionedbetween ethyl acetate and water, washed with water, brine and dried oversodium sulfate. Purification by HPLC (RP) gradient to give 29 mg (14%)of the title compound of Example 104. LRMS (ES+): 504.4 (M+H)⁺

Example 1051-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onebis-trifluoroacetic acid salt

The title compound of Example 105 was prepared following proceduresdescribed previously. LRMS (ES+): 439.4 (M+H)⁺

Example 1061-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(2-(dimethylaminomethyl)imidazol-1′-yl)-2-fluorophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onebis-trifluoroacetic acid salt

The title compound of Example 106 was prepared following proceduresdescribed previously. LRMS (ES+): 500.5 (M+H)⁺

Example 1071-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[4-(2-(dimethylaminomethyl)imidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-onebis-trifluoroacetic acid salt

The title compound of Example 107 was prepared following proceduresdescribed previously. LRMS (ES+): 536.4 (M+H)⁺

Example 1081-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(2-(dimethylaminomethyl)imidazol-1′-yl)-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-onebis-trifluoroacetic acid salt

The title compound of Example 108 was prepared following proceduresdescribed previously. LRMS (ES+): 501.5 (M+H)⁺.

Example 1091-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-(4-bromophenyl)-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one,trifluoroacetic acid salt

The title compound of Example 109 was prepared following proceduresdescribed previously. HRMS (C₂₀H₁₇N₅O₂Br)⁺: 438.0557 m/z.

The following tables contain representative examples of the presentinvention. Each entry in each table is intended to be paired with eachformulae at the start of the table. For example, in Tables 1 and 2,example 1 is intended to be paired with each of the formulae.

The following nomenclature is intended for group A in the followingtables.

TABLE 1

-   Z is CR^(1a);-   G is selected from:    -   4-(methoxy)phenyl;    -   2-(aminomethyl)phenyl;    -   3-(aminomethyl)phenyl;    -   2-(aminomethyl)-3-fluorophenyl;    -   2-(aminomethyl)-4-fluorophenyl;    -   2-(aminomethyl)-5-fluorophenyl;    -   2-(aminomethyl)-6-fluorophenyl;    -   3-amino-phthalazin-5-yl;    -   3-amino-phthalazin-6-yl;    -   1-aminoisoquinolin-6-yl;    -   1-aminoisoquinolin-7-yl;    -   4-aminoquinazol-6-yl;    -   4-aminoquinazol-7-yl;    -   3-aminobenzisoxazol-5-yl;    -   3-aminobenzisoxazol-6-yl;    -   3-aminoisobenzazol-5-yl; and,    -   3-aminoisobenzazaol-6-yl;

Ex# R^(1a) A B 1 CH3 phenyl 2-(aminosulfonyl)phenyl 2 CH3 phenyl2-(methylaminosulfonyl)phenyl 3 CH3 phenyl 1-pyrrolidinocarbonyl 4 CH3phenyl 2-(methylsulfonyl)phenyl 5 CH3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 6 CH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl 7CH3 phenyl 1-methyl-2-imidazolyl 8 CH3 phenyl 2-methyl-1-imidazolyl 9CH3 phenyl 2-(dimethylaminomethyl)-1- imidazolyl 10 CH3 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 11 CH3 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 12 CH3 phenyl 2-(N-(cyclopentyl)-aminomethyl)phenyl 13 CH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-methyl)phenyl 14 CH3 2-pyridyl 2-(aminosulfonyl)phenyl 15 CH3 2-pyridyl2-(methylaminosulfonyl)phenyl 16 CH3 2-pyridyl 1-pyrrolidinocarbonyl 17CH3 2-pyridyl 2-(methylsulfonyl)phenyl 18 CH3 2-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 19 CH3 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 20 CH3 2-pyridyl 1-methyl-2-imidazolyl 21CH3 2-pyridyl 2-methyl-1-imidazolyl 22 CH3 2-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 23 CH3 2-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 24 CH3 2-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 25 CH3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 26 CH3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 27 CH3 3-pyridyl2-(aminosulfonyl)phenyl 28 CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl29 CH3 3-pyridyl 1-pyrrolidinocarbonyl 30 CH3 3-pyridyl2-(methylsulfonyl)phenyl 31 CH3 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 32 CH3 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 33 CH3 3-pyridyl 1-methyl-2-imidazolyl 34CH3 3-pyridyl 2-methyl-1-imidazolyl 35 CH3 3-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 36 CH3 3-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 37 CH3 3-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 38 CH3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 39 CH3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 40 CH3 2-pyrimidyl2-(aminosulfonyl)phenyl 41 CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl42 CH3 2-pyrimidyl 1-pyrrolidinocarbonyl 43 CH3 2-pyrimidyl2-(methylsulfonyl)phenyl 44 CH3 2-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 45 CH3 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 46 CH3 2-pyrimidyl 1-methyl-2-imidazolyl47 CH3 2-pyrimidyl 2-methyl-1-imidazolyl 48 CH3 2-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 49 CH3 2-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 50 CH3 2-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 51 CH3 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 52 CH3 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 53 CH3 5-pyrimidyl2-(aminosulfonyl)phenyl 54 CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl55 CH3 5-pyrimidyl 1-pyrrolidinocarbonyl 56 CH3 5-pyrimidyl2-(methylsulfonyl)phenyl 57 CH3 5-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 58 CH3 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 59 CH3 5-pyrimidyl 1-methyl-2-imidazolyl60 CH3 5-pyrimidyl 2-methyl-1-imidazolyl 61 CH3 5-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 62 CH3 5-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 63 CH3 5-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 64 CH3 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 65 CH3 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 66 CH3 2-Cl-phenyl2-(aminosulfonyl)phenyl 67 CH3 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl68 CH3 2-Cl-phenyl 1-pyrrolidinocarbonyl 69 CH3 2-Cl-phenyl2-(methylsulfonyl)phenyl 70 CH3 2-Cl-phenyl 2-(N,N-dimethylaminomethyl)phenyl 71 CH3 2-Cl-phenyl2-(N-pyrrolidinylmethyl)phenyl 72 CH3 2-Cl-phenyl 1-methyl-2-imidazolyl73 CH3 2-Cl-phenyl 2-methyl-1-imidazolyl 74 CH3 2-Cl-phenyl2-(dimethylaminomethyl)-1- imidazolyl 75 CH3 2-Cl-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 76 CH3 2-Cl-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 77 CH3 2-Cl-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 78 CH3 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 79 CH3 2-F-phenyl2-(aminosulfonyl)phenyl 80 CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl81 CH3 2-F-phenyl 1-pyrrolidinocarbonyl 82 CH3 2-F-phenyl2-(methylsulfonyl)phenyl 83 CH3 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 84 CH3 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 85 CH3 2-F-phenyl 1-methyl-2-imidazolyl86 CH3 2-F-phenyl 2-methyl-1-imidazolyl 87 CH3 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 88 CH3 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 89 CH3 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 90 CH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 91 CH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 92 CH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 93 CH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 94 CH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl95 CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 96 CH3 2,6-diF-phenyl2-(N,N- dimethylaminomethyl)phenyl 97 CH3 2,6-diF-phenyl2-(N-pyrrolidinylmethyl)phenyl 98 CH3 2,6-diF-phenyl1-methyl-2-imidazolyl 99 CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 100CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 101 CH32,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 102 CH32,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 103 CH32,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 104 CH32,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 105 CH2CH3phenyl 2-(aminosulfonyl)phenyl 106 CH2CH3 phenyl2-(methylaminosulfonyl)phenyl 107 CH2CH3 phenyl 1-pyrrolidinocarbonyl108 CH2CH3 phenyl 2-(methylsulfonyl)phenyl 109 CH2CH3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 110 CH2CH3 phenyl2-(N-pyrrolidinylmethyl)phenyl 111 CH2CH3 phenyl 1-methyl-2-imidazolyl112 CH2CH3 phenyl 2-methyl-1-imidazolyl 113 CH2CH3 phenyl2-(dimethylaminomethyl)-1- imidazolyl 114 CH2CH3 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 115 CH2CH3 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 116 CH2CH3 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 117 CH2CH3 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 118 CH2CH3 2-pyridyl2-(aminosulfonyl)phenyl 119 CH2CH3 2-pyridyl2-(methylaminosulfonyl)phenyl 120 CH2CH3 2-pyridyl 1-pyrrolidinocarbonyl121 CH2CH3 2-pyridyl 2-(methylsulfonyl)phenyl 122 CH2CH3 2-pyridyl2-(N,N- dimethylaminomethyl)phenyl 123 CH2CH3 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 124 CH2CH3 2-pyridyl1-methyl-2-imidazolyl 125 CH2CH3 2-pyridyl 2-methyl-1-imidazolyl 126CH2CH3 2-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 127 CH2CH32-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 128 CH2CH32-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 129 CH2CH3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 130 CH2CH3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 131 CH2CH3 3-pyridyl2-(aminosulfonyl)phenyl 132 CH2CH3 3-pyridyl2-(methylaminosulfonyl)phenyl 133 CH2CH3 3-pyridyl 1-pyrrolidinocarbonyl134 CH2CH3 3-pyridyl 2-(methylsulfonyl)phenyl 135 CH2CH3 3-pyridyl2-(N,N- dimethylaminomethyl)phenyl 136 CH2CH3 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 137 CH2CH3 3-pyridyl1-methyl-2-imidazolyl 138 CH2CH3 3-pyridyl 2-methyl-1-imidazolyl 139CH2CH3 3-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 140 CH2CH33-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 141 CH2CH33-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 142 CH2CH3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 143 CH2CH3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 144 CH2CH3 2-pyrimidyl2-(aminosulfonyl)phenyl 145 CH2CH3 2-pyrimidyl2-(methylaminosulfonyl)phenyl 146 CH2CH3 2-pyrimidyl1-pyrrolidinocarbonyl 147 CH2CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl148 CH2CH3 2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 149 CH2CH32-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 150 CH2CH3 2-pyrimidyl1-methyl-2-imidazolyl 151 CH2CH3 2-pyrimidyl 2-methyl-1-imidazolyl 152CH2CH3 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 153 CH2CH32-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 154 CH2CH32-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 155 CH2CH3 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 156 CH2CH3 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 157 CH2CH3 5-pyrimidyl2-(aminosulfonyl)phenyl 158 CH2CH3 5-pyrimidyl2-(methylaminosulfonyl)phenyl 159 CH2CH3 5-pyrimidyl1-pyrrolidinocarbonyl 160 CH2CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl161 CH2CH3 5-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 162 CH2CH35-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 163 CH2CH3 5-pyrimidyl1-methyl-2-imidazolyl 164 CH2CH3 5-pyrimidyl 2-methyl-1-imidazolyl 165CH2CH3 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 166 CH2CH35-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 167 CH2CH35-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 168 CH2CH3 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 169 CH2CH3 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 170 CH2CH3 2-Cl-phenyl2-(aminosulfonyl)phenyl 171 CH2CH3 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 172 CH2CH3 2-Cl-phenyl1-pyrrolidinocarbonyl 173 CH2CH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl174 CH2CH3 2-Cl-phenyl 2-(N,N- dimethylaminomethyl)phenyl 175 CH2CH32-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl 176 CH2CH3 2-Cl-phenyl1-methyl-2-imidazolyl 177 CH2CH3 2-Cl-phenyl 2-methyl-1-imidazolyl 178CH2CH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 179 CH2CH32-Cl-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 180 CH2CH32-Cl-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 181 CH2CH3 2-Cl-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 182 CH2CH3 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 183 CH2CH3 2-F-phenyl2-(aminosulfonyl)phenyl 184 CH2CH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 185 CH2CH3 2-F-phenyl1-pyrrolidinocarbonyl 186 CH2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl 187CH2CH3 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 188 CH2CH32-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 189 CH2CH3 2-F-phenyl1-methyl-2-imidazolyl 190 CH2CH3 2-F-phenyl 2-methyl-1-imidazolyl 191CH2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 192 CH2CH32-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 193 CH2CH32-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 194 CH2CH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 195 CH2CH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 196 CH2CH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 197 CH2CH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 198 CH2CH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 199 CH2CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl200 CH2CH3 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 201 CH2CH32,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 202 CH2CH3 2,6-diF-phenyl1-methyl-2-imidazolyl 203 CH2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl204 CH2CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 205CH2CH3 2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 206CH2CH3 2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 207 CH2CH32,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 208 CH2CH32,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 209 CF3phenyl 2-(aminosulfonyl)phenyl 210 CF3 phenyl2-(methylaminosulfonyl)phenyl 211 CF3 phenyl 1-pyrrolidinocarbonyl 212CF3 phenyl 2-(methylsulfonyl)phenyl 213 CF3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 214 CF3 phenyl 2-(N-pyrrolidinylmethyl)phenyl215 CF3 phenyl 1-methyl-2-imidazolyl 216 CF3 phenyl2-methyl-1-imidazolyl 217 CF3 phenyl 2-(dimethylaminomethyl)-1-imidazolyl 218 CF3 phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl219 CF3 phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 220 CF3 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 221 CF3 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 222 CF3 2-pyridyl2-(aminosulfonyl)phenyl 223 CF3 2-pyridyl 2-(methylaminosulfonyl)phenyl224 CF3 2-pyridyl 1-pyrrolidinocarbonyl 225 CF3 2-pyridyl2-(methylsulfonyl)phenyl 226 CF3 2-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 227 CF3 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 228 CF3 2-pyridyl 1-methyl-2-imidazolyl229 CF3 2-pyridyl 2-methyl-1-imidazolyl 230 CF3 2-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 231 CF3 2-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 232 CF3 2-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 233 CF3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 234 CF3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 235 CF3 3-pyridyl2-(aminosulfonyl)phenyl 236 CF3 3-pyridyl 2-(methylaminosulfonyl)phenyl237 CF3 3-pyridyl 1-pyrrolidinocarbonyl 238 CF3 3-pyridyl2-(methylsulfonyl)phenyl 239 CF3 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 240 CF3 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 241 CF3 3-pyridyl 1-methyl-2-imidazolyl242 CF3 3-pyridyl 2-methyl-1-imidazolyl 243 CF3 3-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 244 CF3 3-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 245 CF3 3-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 246 CF3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 247 CF3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 248 CF3 2-pyrimidyl2-(aminosulfonyl)phenyl 249 CF3 2-pyrimidyl2-(methylaminosulfonyl)phenyl 250 CF3 2-pyrimidyl 1-pyrrolidinocarbonyl251 CF3 2-pyrimidyl 2-(methylsulfonyl)phenyl 252 CF3 2-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 253 CF3 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 254 CF3 2-pyrimidyl 1-methyl-2-imidazolyl255 CF3 2-pyrimidyl 2-methyl-1-imidazolyl 256 CF3 2-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 257 CF3 2-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 258 CF3 2-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 259 CF3 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 260 CF3 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 261 CF3 5-pyrimidyl2-(aminosulfonyl)phenyl 262 CF3 5-pyrimidyl2-(methylaminosulfonyl)phenyl 263 CF3 5-pyrimidyl 1-pyrrolidinocarbonyl264 CF3 5-pyrimidyl 2-(methylsulfonyl)phenyl 265 CF3 5-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 266 CF3 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 267 CF3 5-pyrimidyl 1-methyl-2-imidazolyl268 CF3 5-pyrimidyl 2-methyl-1-imidazolyl 269 CF3 5-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 270 CF3 5-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 271 CF3 5-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 272 CF3 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 273 CF3 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 274 CF3 2-Cl-phenyl2-(aminosulfonyl)phenyl 275 CF3 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 276 CF3 2-Cl-phenyl 1-pyrrolidinocarbonyl277 CF3 2-Cl-phenyl 2-(methylsulfonyl)phenyl 278 CF3 2-Cl-phenyl 2-(N,N-dimethylaminomethyl)phenyl 279 CF3 2-Cl-phenyl2-(N-pyrrolidinylmethyl)phenyl 280 CF3 2-Cl-phenyl 1-methyl-2-imidazolyl281 CF3 2-Cl-phenyl 2-methyl-1-imidazolyl 282 CF3 2-Cl-phenyl2-(dimethylaminomethyl)-1- imidazolyl 283 CF3 2-Cl-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 284 CF3 2-Cl-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 285 CF3 2-Cl-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 286 CF3 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 287 CF3 2-F-phenyl2-(aminosulfonyl)phenyl 288 CF3 2-F-phenyl 2-(methylaminosulfonyl)phenyl289 CF3 2-F-phenyl 1-pyrrolidinocarbonyl 290 CF3 2-F-phenyl2-(methylsulfonyl)phenyl 291 CF3 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 292 CF3 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 293 CF3 2-F-phenyl 1-methyl-2-imidazolyl294 CF3 2-F-phenyl 2-methyl-1-imidazolyl 295 CF3 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 296 CF3 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 297 CF3 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 298 CF3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 299 CF3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 300 CF3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 301 CF3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 302 CF3 2,6-diF-phenyl1-pyrrolidinocarbonyl 303 CF3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl304 CF3 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 305 CF32,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 306 CF3 2,6-diF-phenyl1-methyl-2-imidazolyl 307 CF3 2,6-diF-phenyl 2-methyl-1-imidazolyl 308CF3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 309 CF32,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 310 CF32,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 311 CF32,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 312 CF32,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 313 SCH3phenyl 2-(aminosulfonyl)phenyl 314 SCH3 phenyl2-(methylaminosulfonyl)phenyl 315 SCH3 phenyl 1-pyrrolidinocarbonyl 316SCH3 phenyl 2-(methylsulfonyl)phenyl 317 SCH3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 318 SCH3 phenyl2-(N-pyrrolidinylmethyl)phenyl 319 SCH3 phenyl 1-methyl-2-imidazolyl 320SCH3 phenyl 2-methyl-1-imidazolyl 321 SCH3 phenyl2-(dimethylaminomethyl)-1- imidazolyl 322 SCH3 phenyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 323 SCH3 phenyl 2-(N-(cyclobutyl)-aminomethyl)phenyl 324 SCH3 phenyl 2-(N-(cyclopentyl)-aminomethyl)phenyl 325 SCH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-methyl)phenyl 326 SCH3 2-pyridyl 2-(aminosulfonyl)phenyl 327 SCH32-pyridyl 2-(methylaminosulfonyl)phenyl 328 SCH3 2-pyridyl1-pyrrolidinocarbonyl 329 SCH3 2-pyridyl 2-(methylsulfonyl)phenyl 330SCH3 2-pyridyl 2-(N,N- dimethylaminomethyl)phenyl 331 SCH3 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 332 SCH3 2-pyridyl 1-methyl-2-imidazolyl333 SCH3 2-pyridyl 2-methyl-1-imidazolyl 334 SCH3 2-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 335 SCH3 2-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 336 SCH3 2-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 337 SCH3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 338 SCH3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 339 SCH3 3-pyridyl2-(aminosulfonyl)phenyl 340 SCH3 3-pyridyl 2-(methylaminosulfonyl)phenyl341 SCH3 3-pyridyl 1-pyrrolidinocarbonyl 342 SCH3 3-pyridyl2-(methylsulfonyl)phenyl 343 SCH3 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 344 SCH3 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 345 SCH3 3-pyridyl 1-methyl-2-imidazolyl346 SCH3 3-pyridyl 2-methyl-1-imidazolyl 347 SCH3 3-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 348 SCH3 3-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 349 SCH3 3-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 350 SCH3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 351 SCH3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 352 SCH3 2-pyrimidyl2-(aminosulfonyl)phenyl 353 SCH3 2-pyrimidyl2-(methylaminosulfonyl)phenyl 354 SCH3 2-pyrimidyl 1-pyrrolidinocarbonyl355 SCH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 356 SCH3 2-pyrimidyl2-(N,N- dimethylaminomethyl)phenyl 357 SCH3 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 358 SCH3 2-pyrimidyl1-methyl-2-imidazolyl 359 SCH3 2-pyrimidyl 2-methyl-1-imidazolyl 360SCH3 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 361 SCH32-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 362 SCH32-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 363 SCH3 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 364 SCH3 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 365 SCH3 5-pyrimidyl2-(aminosulfonyl)phenyl 366 SCH3 5-pyrimidyl2-(methylaminosulfonyl)phenyl 367 SCH3 5-pyrimidyl 1-pyrrolidinocarbonyl368 SCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 369 SCH3 5-pyrimidyl2-(N,N- dimethylaminomethyl)phenyl 370 SCH3 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 371 SCH3 5-pyrimidyl1-methyl-2-imidazolyl 372 SCH3 5-pyrimidyl 2-methyl-1-imidazolyl 373SCH3 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 374 SCH35-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 375 SCH35-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 376 SCH3 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 377 SCH3 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 378 SCH3 2-Cl-phenyl2-(aminosulfonyl)phenyl 379 SCH3 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 380 SCH3 2-Cl-phenyl 1-pyrrolidinocarbonyl381 SCH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl 382 SCH3 2-Cl-phenyl2-(N,N- dimethylaminomethyl)phenyl 383 SCH3 2-Cl-phenyl2-(N-pyrrolidinylmethyl)phenyl 384 SCH3 2-Cl-phenyl1-methyl-2-imidazolyl 385 SCH3 2-Cl-phenyl 2-methyl-1-imidazolyl 386SCH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 387 SCH32-Cl-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 388 SCH32-Cl-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 389 SCH3 2-Cl-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 390 SCH3 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 391 SCH3 2-F-phenyl2-(aminosulfonyl)phenyl 392 SCH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 393 SCH3 2-F-phenyl 1-pyrrolidinocarbonyl394 SCH3 2-F-phenyl 2-(methylsulfonyl)phenyl 395 SCH3 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 396 SCH3 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 397 SCH3 2-F-phenyl 1-methyl-2-imidazolyl398 SCH3 2-F-phenyl 2-methyl-1-imidazolyl 399 SCH3 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 400 SCH3 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 401 SCH3 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 402 SCH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 403 SCH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 404 SCH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 405 SCH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 406 SCH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 407 SCH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl408 SCH3 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 409 SCH32,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 410 SCH3 2,6-diF-phenyl1-methyl-2-imidazolyl 411 SCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 412SCH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 413 SCH32,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 414 SCH32,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 415 SCH32,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 416 SCH32,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 417 SOCH3phenyl 2-(aminosulfonyl)phenyl 418 SOCH3 phenyl2-(methylaminosulfonyl)phenyl 419 SOCH3 phenyl 1-pyrrolidinocarbonyl 420SOCH3 phenyl 2-(methylsulfonyl)phenyl 421 SOCH3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 422 SOCH3 phenyl2-(N-pyrrolidinylmethyl)phenyl 423 SOCH3 phenyl 1-methyl-2-imidazolyl424 SOCH3 phenyl 2-methyl-1-imidazolyl 425 SOCH3 phenyl2-(dimethylaminomethyl)-1- imidazolyl 426 SOCH3 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 427 SOCH3 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 428 SOCH3 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 429 SOCH3 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 430 SOCH3 2-pyridyl2-(aminosulfonyl)phenyl 431 SOCH3 2-pyridyl2-(methylaminosulfonyl)phenyl 432 SOCH3 2-pyridyl 1-pyrrolidinocarbonyl433 SOCH3 2-pyridyl 2-(methylsulfonyl)phenyl 434 SOCH3 2-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 435 SOCH3 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 436 SOCH3 2-pyridyl 1-methyl-2-imidazolyl437 SOCH3 2-pyridyl 2-methyl-1-imidazolyl 438 SOCH3 2-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 439 SOCH3 2-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 440 SOCH3 2-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 441 SOCH3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 442 SOCH3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 443 SOCH3 3-pyridyl2-(aminosulfonyl)phenyl 444 SOCH3 3-pyridyl2-(methylaminosulfonyl)phenyl 445 SOCH3 3-pyridyl 1-pyrrolidinocarbonyl446 SOCH3 3-pyridyl 2-(methylsulfonyl)phenyl 447 SOCH3 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 448 SOCH3 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 449 SOCH3 3-pyridyl 1-methyl-2-imidazolyl450 SOCH3 3-pyridyl 2-methyl-1-imidazolyl 451 SOCH3 3-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 452 SOCH3 3-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 453 SOCH3 3-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 454 SOCH3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 455 SOCH3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 456 SOCH3 2-pyrimidyl2-(aminosulfonyl)phenyl 457 SOCH3 2-pyrimidyl2-(methylaminosulfonyl)phenyl 458 SOCH3 2-pyrimidyl1-pyrrolidinocarbonyl 459 SOCH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 460SOCH3 2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 461 SOCH32-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 462 SOCH3 2-pyrimidyl1-methyl-2-imidazolyl 463 SOCH3 2-pyrimidyl 2-methyl-1-imidazolyl 464SOCH3 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 465 SOCH32-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 466 SOCH32-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 467 SOCH3 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 468 SOCH3 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 469 SOCH3 5-pyrimidyl2-(aminosulfonyl)phenyl 470 SOCH3 5-pyrimidyl2-(methylaminosulfonyl)phenyl 471 SOCH3 5-pyrimidyl1-pyrrolidinocarbonyl 472 SOCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 473SOCH3 5-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 474 SOCH35-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 475 SOCH3 5-pyrimidyl1-methyl-2-imidazolyl 476 SOCH3 5-pyrimidyl 2-methyl-1-imidazolyl 477SOCH3 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 478 SOCH35-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 479 SOCH35-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 480 SOCH3 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 481 SOCH3 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 482 SOCH3 2-Cl-phenyl2-(aminosulfonyl)phenyl 483 SOCH3 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 484 SOCH3 2-Cl-phenyl1-pyrrolidinocarbonyl 485 SOCH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl 486SOCH3 2-Cl-phenyl 2-(N,N- dimethylaminomethyl)phenyl 487 SOCH32-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl 488 SOCH3 2-Cl-phenyl1-methyl-2-imidazolyl 489 SOCH3 2-Cl-phenyl 2-methyl-1-imidazolyl 490SOCH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 491 SOCH32-Cl-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 492 SOCH32-Cl-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 493 SOCH3 2-Cl-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 494 SOCH3 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 495 SOCH3 2-F-phenyl2-(aminosulfonyl)phenyl 496 SOCH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 497 SOCH3 2-F-phenyl 1-pyrrolidinocarbonyl498 SOCH3 2-F-phenyl 2-(methylsulfonyl)phenyl 499 SOCH3 2-F-phenyl2-(N,N- dimethylaminomethyl)phenyl 500 SOCH3 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 501 SOCH3 2-F-phenyl1-methyl-2-imidazolyl 502 SOCH3 2-F-phenyl 2-methyl-1-imidazolyl 503SOCH3 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 504 SOCH32-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 505 SOCH32-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 506 SOCH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 507 SOCH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 508 SOCH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 509 SOCH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 510 SOCH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 511 SOCH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl512 SOCH3 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 513 SOCH32,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 514 SOCH3 2,6-diF-phenyl1-methyl-2-imidazolyl 515 SOCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 516SOCH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 517 SOCH32,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 518 SOCH32,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 519 SOCH32,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 520 SOCH32,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 521 SO2CH3phenyl 2-(aminosulfonyl)phenyl 522 SO2CH3 phenyl2-(methylaminosulfonyl)phenyl 523 SO2CH3 phenyl 1-pyrrolidinocarbonyl524 SO2CH3 phenyl 2-(methylsulfonyl)phenyl 525 SO2CH3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 526 SO2CH3 phenyl2-(N-pyrrolidinylmethyl)phenyl 527 SO2CH3 phenyl 1-methyl-2-imidazolyl528 SO2CH3 phenyl 2-methyl-1-imidazolyl 529 SO2CH3 phenyl2-(dimethylaminomethyl)-1- imidazolyl 530 SO2CH3 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 531 SO2CH3 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 532 SO2CH3 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 533 SO2CH3 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 534 SO2CH3 2-pyridyl2-(aminosulfonyl)phenyl 535 SO2CH3 2-pyridyl2-(methylaminosulfonyl)phenyl 536 SO2CH3 2-pyridyl 1-pyrrolidinocarbonyl537 SO2CH3 2-pyridyl 2-(methylsulfonyl)phenyl 538 SO2CH3 2-pyridyl2-(N,N- dimethylaminomethyl)phenyl 539 SO2CH3 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 540 SO2CH3 2-pyridyl1-methyl-2-imidazolyl 541 SO2CH3 2-pyridyl 2-methyl-1-imidazolyl 542SO2CH3 2-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 543 SO2CH32-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 544 SO2CH32-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 545 SO2CH3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 546 SO2CH3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 547 SO2CH3 3-pyridyl2-(aminosulfonyl)phenyl 548 SO2CH3 3-pyridyl2-(methylaminosulfonyl)phenyl 549 SO2CH3 3-pyridyl 1-pyrrolidinocarbonyl550 SO2CH3 3-pyridyl 2-(methylsulfonyl)phenyl 551 SO2CH3 3-pyridyl2-(N,N- dimethylaminomethyl)phenyl 552 SO2CH3 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 553 SO2CH3 3-pyridyl1-methyl-2-imidazolyl 554 SO2CH3 3-pyridyl 2-methyl-1-imidazolyl 555SO2CH3 3-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 556 SO2CH33-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 557 SO2CH33-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 558 SO2CH3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 559 SO2CH3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 560 SO2CH3 2-pyrimidyl2-(aminosulfonyl)phenyl 561 SO2CH3 2-pyrimidyl2-(methylaminosulfonyl)phenyl 562 SO2CH3 2-pyrimidyl1-pyrrolidinocarbonyl 563 SO2CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl564 SO2CH3 2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 565 SO2CH32-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 566 SO2CH3 2-pyrimidyl1-methyl-2-imidazolyl 567 SO2CH3 2-pyrimidyl 2-methyl-1-imidazolyl 568SO2CH3 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 569 SO2CH32-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 570 SO2CH32-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 571 SO2CH3 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 572 SO2CH3 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 573 SO2CH3 5-pyrimidyl2-(aminosulfonyl)phenyl 574 SO2CH3 5-pyrimidyl2-(methylaminosulfonyl)phenyl 575 SO2CH3 5-pyrimidyl1-pyrrolidinocarbonyl 576 SO2CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl577 SO2CH3 5-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 578 SO2CH35-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 579 SO2CH3 5-pyrimidyl1-methyl-2-imidazolyl 580 SO2CH3 5-pyrimidyl 2-methyl-1-imidazolyl 581SO2CH3 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 582 SO2CH35-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 583 SO2CH35-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 584 SO2CH3 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 585 SO2CH3 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 586 SO2CH3 2-Cl-phenyl2-(aminosulfonyl)phenyl 587 SO2CH3 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 588 SO2CH3 2-Cl-phenyl1-pyrrolidinocarbonyl 589 SO2CH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl590 SO2CH3 2-Cl-phenyl 2-(N,N- dimethylaminomethyl)phenyl 591 SO2CH32-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl 592 SO2CH3 2-Cl-phenyl1-methyl-2-imidazolyl 593 SO2CH3 2-Cl-phenyl 2-methyl-1-imidazolyl 594SO2CH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 595 SO2CH32-Cl-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 596 SO2CH32-Cl-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 597 SO2CH3 2-Cl-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 598 SO2CH3 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 599 SO2CH3 2-F-phenyl2-(aminosulfonyl)phenyl 600 SO2CH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 601 SO2CH3 2-F-phenyl1-pyrrolidinocarbonyl 602 SO2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl 603SO2CH3 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 604 SO2CH32-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 605 SO2CH3 2-F-phenyl1-methyl-2-imidazolyl 606 SO2CH3 2-F-phenyl 2-methyl-1-imidazolyl 607SO2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 608 SO2CH32-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 609 SO2CH32-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 610 SO2CH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 611 SO2CH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 612 SO2CH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 613 SO2CH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 614 SO2CH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 615 SO2CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl616 SO2CH3 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 617 SO2CH32,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 618 SO2CH3 2,6-diF-phenyl1-methyl-2-imidazolyl 619 SO2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl620 SO2CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 621SO2CH3 2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 622SO2CH3 2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 623 SO2CH32,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 624 SO2CH32,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 625 Cl phenyl2-(aminosulfonyl)phenyl 626 Cl phenyl 2-(methylaminosulfonyl)phenyl 627Cl phenyl 1-pyrrolidinocarbonyl 628 Cl phenyl 2-(methylsulfonyl)phenyl629 Cl phenyl 2-(N,N- dimethylaminomethyl)phenyl 630 Cl phenyl2-(N-pyrrolidinylmethyl)phenyl 631 Cl phenyl 1-methyl-2-imidazolyl 632Cl phenyl 2-methyl-1-imidazolyl 633 Cl phenyl 2-(dimethylaminomethyl)-1-imidazolyl 634 Cl phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl635 Cl phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 636 Cl phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 637 Cl phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 638 Cl 2-pyridyl2-(aminosulfonyl)phenyl 639 Cl 2-pyridyl 2-(methylaminosulfonyl)phenyl640 Cl 2-pyridyl 1-pyrrolidinocarbonyl 641 Cl 2-pyridyl2-(methylsulfonyl)phenyl 642 Cl 2-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 643 Cl 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 644 Cl 2-pyridyl 1-methyl-2-imidazolyl645 Cl 2-pyridyl 2-methyl-1-imidazolyl 646 Cl 2-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 647 Cl 2-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 648 Cl 2-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 649 Cl 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 650 Cl 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 651 Cl 3-pyridyl2-(aminosulfonyl)phenyl 652 Cl 3-pyridyl 2-(methylaminosulfonyl)phenyl653 Cl 3-pyridyl 1-pyrrolidinocarbonyl 654 Cl 3-pyridyl2-(methylsulfonyl)phenyl 655 Cl 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 656 Cl 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 657 Cl 3-pyridyl 1-methyl-2-imidazolyl658 Cl 3-pyridyl 2-methyl-1-imidazolyl 659 Cl 3-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 660 Cl 3-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 661 Cl 3-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 662 Cl 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 663 Cl 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 664 Cl 2-pyrimidyl2-(aminosulfonyl)phenyl 665 Cl 2-pyrimidyl 2-(methylaminosulfonyl)phenyl666 Cl 2-pyrimidyl 1-pyrrolidinocarbonyl 667 Cl 2-pyrimidyl2-(methylsulfonyl)phenyl 668 Cl 2-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 669 Cl 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 670 Cl 2-pyrimidyl 1-methyl-2-imidazolyl671 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 672 Cl 2-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 673 Cl 2-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 674 Cl 2-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 675 Cl 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 676 Cl 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 677 Cl 5-pyrimidyl2-(aminosulfonyl)phenyl 678 Cl 5-pyrimidyl 2-(methylaminosulfonyl)phenyl679 Cl 5-pyrimidyl 1-pyrrolidinocarbonyl 680 Cl 5-pyrimidyl2-(methylsulfonyl)phenyl 681 Cl 5-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 682 Cl 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 683 Cl 5-pyrimidyl 1-methyl-2-imidazolyl684 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 685 Cl 5-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 686 Cl 5-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 687 Cl 5-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 688 Cl 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 689 Cl 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 690 Cl 2-Cl-phenyl2-(aminosulfonyl)phenyl 691 Cl 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl692 Cl 2-Cl-phenyl 1-pyrrolidinocarbonyl 693 Cl 2-Cl-phenyl2-(methylsulfonyl)phenyl 694 Cl 2-Cl-phenyl 2-(N,N-dimethylaminomethyl)phenyl 695 Cl 2-Cl-phenyl2-(N-pyrrolidinylmethyl)phenyl 696 Cl 2-Cl-phenyl 1-methyl-2-imidazolyl697 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl 698 Cl 2-Cl-phenyl2-(dimethylaminomethyl)-1- imidazolyl 699 Cl 2-Cl-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 700 Cl 2-Cl-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 701 Cl 2-Cl-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 702 Cl 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 703 Cl 2-F-phenyl2-(aminosulfonyl)phenyl 704 Cl 2-F-phenyl 2-(methylaminosulfonyl)phenyl705 Cl 2-F-phenyl 1-pyrrolidinocarbonyl 706 Cl 2-F-phenyl2-(methylsulfonyl)phenyl 707 Cl 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 708 Cl 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 709 Cl 2-F-phenyl 1-methyl-2-imidazolyl710 Cl 2-F-phenyl 2-methyl-1-imidazolyl 711 Cl 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 712 Cl 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 713 Cl 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 714 Cl 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 715 Cl 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 716 Cl 2,6-diF-phenyl2-(aminosulfonyl)phenyl 717 Cl 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 718 Cl 2,6-diF-phenyl1-pyrrolidinocarbonyl 719 Cl 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 720Cl 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 721 Cl2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 722 Cl 2,6-diF-phenyl1-methyl-2-imidazolyl 723 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 724 Cl2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 725 Cl2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 726 Cl2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 727 Cl2,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 728 Cl2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 729 F phenyl2-(aminosulfonyl)phenyl 730 F phenyl 2-(methylaminosulfonyl)phenyl 731 Fphenyl 1-pyrrolidinocarbonyl 732 F phenyl 2-(methylsulfonyl)phenyl 733 Fphenyl 2-(N,N- dimethylaminomethyl)phenyl 734 F phenyl2-(N-pyrrolidinylmethyl)phenyl 735 F phenyl 1-methyl-2-imidazolyl 736 Fphenyl 2-methyl-1-imidazolyl 737 F phenyl 2-(dimethylaminomethyl)-1-imidazolyl 738 F phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 739F phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 740 F phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 741 F phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 742 F 2-pyridyl2-(aminosulfonyl)phenyl 743 F 2-pyridyl 2-(methylaminosulfonyl)phenyl744 F 2-pyridyl 1-pyrrolidinocarbonyl 745 F 2-pyridyl2-(methylsulfonyl)phenyl 746 F 2-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 747 F 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 748 F 2-pyridyl 1-methyl-2-imidazolyl 749F 2-pyridyl 2-methyl-1-imidazolyl 750 F 2-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 751 F 2-pyridyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 752 F 2-pyridyl 2-(N-(cyclobutyl)-aminomethyl)phenyl 753 F 2-pyridyl 2-(N-(cyclopentyl)-aminomethyl)phenyl 754 F 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-methyl)phenyl 755 F 3-pyridyl 2-(aminosulfonyl)phenyl 756 F 3-pyridyl2-(methylaminosulfonyl)phenyl 757 F 3-pyridyl 1-pyrrolidinocarbonyl 758F 3-pyridyl 2-(methylsulfonyl)phenyl 759 F 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 760 F 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 761 F 3-pyridyl 1-methyl-2-imidazolyl 762F 3-pyridyl 2-methyl-1-imidazolyl 763 F 3-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 764 F 3-pyridyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 765 F 3-pyridyl 2-(N-(cyclobutyl)-aminomethyl)phenyl 766 F 3-pyridyl 2-(N-(cyclopentyl)-aminomethyl)phenyl 767 F 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-methyl)phenyl 768 F 2-pyrimidyl 2-(aminosulfonyl)phenyl 769 F2-pyrimidyl 2-(methylaminosulfonyl)phenyl 770 F 2-pyrimidyl1-pyrrolidinocarbonyl 771 F 2-pyrimidyl 2-(methylsulfonyl)phenyl 772 F2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 773 F 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 774 F 2-pyrimidyl 1-methyl-2-imidazolyl775 F 2-pyrimidyl 2-methyl-1-imidazolyl 776 F 2-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 777 F 2-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 778 F 2-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 779 F 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 780 F 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 781 F 5-pyrimidyl2-(aminosulfonyl)phenyl 782 F 5-pyrimidyl 2-(methylaminosulfonyl)phenyl783 F 5-pyrimidyl 1-pyrrolidinocarbonyl 784 F 5-pyrimidyl2-(methylsulfonyl)phenyl 785 F 5-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 786 F 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 787 F 5-pyrimidyl 1-methyl-2-imidazolyl788 F 5-pyrimidyl 2-methyl-1-imidazolyl 789 F 5-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 790 F 5-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 791 F 5-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 792 F 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 793 F 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 794 F 2-F-phenyl2-(aminosulfonyl)phenyl 795 F 2-F-phenyl 2-(methylaminosulfonyl)phenyl796 F 2-F-phenyl 1-pyrrolidinocarbonyl 797 F 2-F-phenyl2-(methylsulfonyl)phenyl 798 F 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 799 F 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 800 F 2-F-phenyl 1-methyl-2-imidazolyl801 F 2-F-phenyl 2-methyl-1-imidazolyl 802 F 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 803 F 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 804 F 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 805 F 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 806 F 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 807 F 2-F-phenyl2-(aminosulfonyl)phenyl 808 F 2-F-phenyl 2-(methylaminosulfonyl)phenyl809 F 2-F-phenyl 1-pyrrolidinocarbonyl 810 F 2-F-phenyl2-(methylsulfonyl)phenyl 811 F 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 812 F 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 813 F 2-F-phenyl 1-methyl-2-imidazolyl814 F 2-F-phenyl 2-methyl-1-imidazolyl 815 F 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 816 F 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 817 F 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 818 F 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 819 F 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 820 F 2,6-diF-phenyl2-(aminosulfonyl)phenyl 821 F 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 822 F 2,6-diF-phenyl 1-pyrrolidinocarbonyl823 F 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 824 F 2,6-diF-phenyl2-(N,N- dimethylaminomethyl)phenyl 825 F 2,6-diF-phenyl2-(N-pyrrolidinylmethyl)phenyl 826 F 2,6-diF-phenyl1-methyl-2-imidazolyl 827 F 2,6-diF-phenyl 2-methyl-1-imidazolyl 828 F2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 829 F2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 830 F2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 831 F2,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 832 F2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 833 CO2CH3phenyl 2-(aminosulfonyl)phenyl 834 CO2CH3 phenyl2-(methylaminosulfonyl)phenyl 835 CO2CH3 phenyl 1-pyrrolidinocarbonyl836 CO2CH3 phenyl 2-(methylsulfonyl)phenyl 837 CO2CH3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 838 CO2CH3 phenyl2-(N-pyrrolidinylmethyl)phenyl 839 CO2CH3 phenyl 1-methyl-2-imidazolyl840 CO2CH3 phenyl 2-methyl-1-imidazolyl 841 CO2CH3 phenyl2-(dimethylaminomethyl)-1- imidazolyl 842 CO2CH3 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 843 CO2CH3 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 844 CO2CH3 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 845 CO2CH3 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 846 CO2CH3 2-pyridyl2-(aminosulfonyl)phenyl 847 CO2CH3 2-pyridyl2-(methylaminosulfonyl)phenyl 848 CO2CH3 2-pyridyl 1-pyrrolidinocarbonyl849 CO2CH3 2-pyridyl 2-(methylsulfonyl)phenyl 850 CO2CH3 2-pyridyl2-(N,N- dimethylaminomethyl)phenyl 851 CO2CH3 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 852 CO2CH3 2-pyridyl1-methyl-2-imidazolyl 853 CO2CH3 2-pyridyl 2-methyl-1-imidazolyl 854CO2CH3 2-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 855 CO2CH32-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 856 CO2CH32-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 857 CO2CH3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 858 CO2CH3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 859 CO2CH3 3-pyridyl2-(aminosulfonyl)phenyl 860 CO2CH3 3-pyridyl2-(methylaminosulfonyl)phenyl 861 CO2CH3 3-pyridyl 1-pyrrolidinocarbonyl862 CO2CH3 3-pyridyl 2-(methylsulfonyl)phenyl 863 CO2CH3 3-pyridyl2-(N,N- dimethylaminomethyl)phenyl 864 CO2CH3 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 865 CO2CH3 3-pyridyl1-methyl-2-imidazolyl 866 CO2CH3 3-pyridyl 2-methyl-1-imidazolyl 867CO2CH3 3-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 868 CO2CH33-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 869 CO2CH33-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 870 CO2CH3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 871 CO2CH3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 872 CO2CH3 2-pyrimidyl2-(aminosulfonyl)phenyl 873 CO2CH3 2-pyrimidyl2-(methylaminosulfonyl)phenyl 874 CO2CH3 2-pyrimidyl1-pyrrolidinocarbonyl 875 CO2CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl876 CO2CH3 2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 877 CO2CH32-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 878 CO2CH3 2-pyrimidyl1-methyl-2-imidazolyl 879 CO2CH3 2-pyrimidyl 2-methyl-1-imidazolyl 880CO2CH3 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 881 CO2CH32-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 882 CO2CH32-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 883 CO2CH3 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 884 CO2CH3 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 885 CO2CH3 5-pyrimidyl2-(aminosulfonyl)phenyl 886 CO2CH3 5-pyrimidyl2-(methylaminosulfonyl)phenyl 887 CO2CH3 5-pyrimidyl1-pyrrolidinocarbonyl 888 CO2CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl889 CO2CH3 5-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 890 CO2CH35-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 891 CO2CH3 5-pyrimidyl1-methyl-2-imidazolyl 892 CO2CH3 5-pyrimidyl 2-methyl-1-imidazolyl 893CO2CH3 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 894 CO2CH35-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 895 CO2CH35-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 896 CO2CH3 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 897 CO2CH3 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 898 CO2CH3 2-F-phenyl2-(aminosulfonyl)phenyl 899 CO2CH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 900 CO2CH3 2-F-phenyl1-pyrrolidinocarbonyl 901 CO2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl 902CO2CH3 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 903 CO2CH32-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 904 CO2CH3 2-F-phenyl1-methyl-2-imidazolyl 905 CO2CH3 2-F-phenyl 2-methyl-1-imidazolyl 906CO2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 907 CO2CH32-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 908 CO2CH32-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 909 CO2CH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 910 CO2CH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 911 CO2CH3 2-F-phenyl2-(aminosulfonyl)phenyl 912 CO2CH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 913 CO2CH3 2-F-phenyl1-pyrrolidinocarbonyl 914 CO2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl 915CO2CH3 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 916 CO2CH32-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 917 CO2CH3 2-F-phenyl1-methyl-2-imidazolyl 918 CO2CH3 2-F-phenyl 2-methyl-1-imidazolyl 919CO2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 920 CO2CH32-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 921 CO2CH32-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 922 CO2CH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 923 CO2CH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 924 CO2CH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 925 CO2CH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 926 CO2CH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 927 CO2CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl928 CO2CH3 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 929 CO2CH32,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 930 CO2CH3 2,6-diF-phenyl1-methyl-2-imidazolyl 931 CO2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl932 CO2CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 933CO2CH3 2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 934CO2CH3 2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 935 CO2CH32,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 936 CO2CH32,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 937 CH2OCH3phenyl 2-(aminosulfonyl)phenyl 938 CH2OCH3 phenyl2-(methylaminosulfonyl)phenyl 939 CH2OCH3 phenyl 1-pyrrolidinocarbonyl940 CH2OCH3 phenyl 2-(methylsulfonyl)phenyl 941 CH2OCH3 phenyl 2-(N,N-dimethylaminomethyl)phenyl 942 CH2OCH3 phenyl2-(N-pyrrolidinylmethyl)phenyl 943 CH2OCH3 phenyl 1-methyl-2-imidazolyl944 CH2OCH3 phenyl 2-methyl-1-imidazolyl 945 CH2OCH3 phenyl2-(dimethylaminomethyl)-1- imidazolyl 946 CH2OCH3 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 947 CH2OCH3 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 948 CH2OCH3 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 949 CH2OCH3 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 950 CH2OCH3 2-pyridyl2-(aminosulfonyl)phenyl 951 CH2OCH3 2-pyridyl2-(methylaminosulfonyl)phenyl 952 CH2OCH3 2-pyridyl1-pyrrolidinocarbonyl 953 CH2OCH3 2-pyridyl 2-(methylsulfonyl)phenyl 954CH2OCH3 2-pyridyl 2-(N,N- dimethylaminomethyl)phenyl 955 CH2OCH32-pyridyl 2-(N-pyrrolidinylmethyl)phenyl 956 CH2OCH3 2-pyridyl1-methyl-2-imidazolyl 957 CH2OCH3 2-pyridyl 2-methyl-1-imidazolyl 958CH2OCH3 2-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 959 CH2OCH32-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 960 CH2OCH32-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 961 CH2OCH3 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 962 CH2OCH3 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 963 CH2OCH3 3-pyridyl2-(aminosulfonyl)phenyl 964 CH2OCH3 3-pyridyl2-(methylaminosulfonyl)phenyl 965 CH2OCH3 3-pyridyl1-pyrrolidinocarbonyl 966 CH2OCH3 3-pyridyl 2-(methylsulfonyl)phenyl 967CH2OCH3 3-pyridyl 2-(N,N- dimethylaminomethyl)phenyl 968 CH2OCH33-pyridyl 2-(N-pyrrolidinylmethyl)phenyl 969 CH2OCH3 3-pyridyl1-methyl-2-imidazolyl 970 CH2OCH3 3-pyridyl 2-methyl-1-imidazolyl 971CH2OCH3 3-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 972 CH2OCH33-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 973 CH2OCH33-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 974 CH2OCH3 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 975 CH2OCH3 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 976 CH2OCH3 2-pyrimidyl2-(aminosulfonyl)phenyl 977 CH2OCH3 2-pyrimidyl2-(methylaminosulfonyl)phenyl 978 CH2OCH3 2-pyrimidyl1-pyrrolidinocarbonyl 979 CH2OCH3 2-pyrimidyl 2-(methylsulfonyl)phenyl980 CH2OCH3 2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 981 CH2OCH32-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 982 CH2OCH3 2-pyrimidyl1-methyl-2-imidazolyl 983 CH2OCH3 2-pyrimidyl 2-methyl-1-imidazolyl 984CH2OCH3 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 985 CH2OCH32-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 986 CH2OCH32-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 987 CH2OCH32-pyrimidyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 988 CH2OCH32-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 989 CH2OCH35-pyrimidyl 2-(aminosulfonyl)phenyl 990 CH2OCH3 5-pyrimidyl2-(methylaminosulfonyl)phenyl 991 CH2OCH3 5-pyrimidyl1-pyrrolidinocarbonyl 992 CH2OCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl993 CH2OCH3 5-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 994 CH2OCH35-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 995 CH2OCH3 5-pyrimidyl1-methyl-2-imidazolyl 996 CH2OCH3 5-pyrimidyl 2-methyl-1-imidazolyl 997CH2OCH3 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 998 CH2OCH35-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 999 CH2OCH35-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1000 CH2OCH35-pyrimidyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 1001 CH2OCH35-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1002 CH2OCH32-F-phenyl 2-(aminosulfonyl)phenyl 1003 CH2OCH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 1004 CH2OCH3 2-F-phenyl1-pyrrolidinocarbonyl 1005 CH2OCH3 2-F-phenyl 2-(methylsulfonyl)phenyl1006 CH2OCH3 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1007 CH2OCH32-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1008 CH2OCH3 2-F-phenyl1-methyl-2-imidazolyl 1009 CH2OCH3 2-F-phenyl 2-methyl-1-imidazolyl 1010CH2OCH3 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1011 CH2OCH32-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1012 CH2OCH32-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1013 CH2OCH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1014 CH2OCH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1015 CH2OCH3 2-F-phenyl2-(aminosulfonyl)phenyl 1016 CH2OCH3 2-F-phenyl2-(methylaminosulfonyl)phenyl 1017 CH2OCH3 2-F-phenyl1-pyrrolidinocarbonyl 1018 CH2OCH3 2-F-phenyl 2-(methylsulfonyl)phenyl1019 CH2OCH3 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1020 CH2OCH32-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1021 CH2OCH3 2-F-phenyl1-methyl-2-imidazolyl 1022 CH2OCH3 2-F-phenyl 2-methyl-1-imidazolyl 1023CH2OCH3 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1024 CH2OCH32-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1025 CH2OCH32-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1026 CH2OCH3 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1027 CH2OCH3 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1028 CH2OCH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 1029 CH2OCH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 1030 CH2OCH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 1031 CH2OCH3 2,6-diF-phenyl2-(methylsulfonyl)phenyl 1032 CH2OCH3 2,6-diF-phenyl 2-(N,N-dimethylaminomethyl)phenyl 1033 CH2OCH3 2,6-diF-phenyl2-(N-pyrrolidinylmethyl)phenyl 1034 CH2OCH3 2,6-diF-phenyl1-methyl-2-imidazolyl 1035 CH2OCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl1036 CH2OCH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1037CH2OCH3 2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1038CH2OCH3 2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1039CH2OCH3 2,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 1040CH2OCH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl) - methyl)phenyl 1041CONH2 phenyl 2-(aminosulfonyl)phenyl 1042 CONH2 phenyl2-(methylaminosulfonyl)phenyl 1043 CONH2 phenyl 1-pyrrolidinocarbonyl1044 CONH2 phenyl 2-(methylsulfonyl)phenyl 1045 CONH2 phenyl 2-(N,N-dimethylaminomethyl)phenyl 1046 CONH2 phenyl2-(N-pyrrolidinylmethyl)phenyl 1047 CONH2 phenyl 1-methyl-2-imidazolyl1048 CONH2 phenyl 2-methyl-1-imidazolyl 1049 CONH2 phenyl2-(dimethylaminomethyl)-1- imidazolyl 1050 CONH2 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1051 CONH2 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1052 CONH2 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1053 CONH2 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1054 CONH2 2-pyridyl2-(aminosulfonyl)phenyl 1055 CONH2 2-pyridyl2-(methylaminosulfonyl)phenyl 1056 CONH2 2-pyridyl 1-pyrrolidinocarbonyl1057 CONH2 2-pyridyl 2-(methylsulfonyl)phenyl 1058 CONH2 2-pyridyl2-(N,N- dimethylaminomethyl)phenyl 1059 CONH2 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 1060 CONH2 2-pyridyl1-methyl-2-imidazolyl 1061 CONH2 2-pyridyl 2-methyl-1-imidazolyl 1062CONH2 2-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 1063 CONH22-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1064 CONH22-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1065 CONH2 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1066 CONH2 2-pyridyl2-(N-(3-hydroxypyrrolidinyl) - methyl)phenyl 1067 CONH2 3-pyridyl2-(aminosulfonyl)phenyl 1068 CONH2 3-pyridyl2-(methylaminosulfonyl)phenyl 1069 CONH2 3-pyridyl 1-pyrrolidinocarbonyl1070 CONH2 3-pyridyl 2-(methylsulfonyl)phenyl 1071 CONH2 3-pyridyl2-(N,N- dimethylaminomethyl)phenyl 1072 CONH2 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 1073 CONH2 3-pyridyl1-methyl-2-imidazolyl 1074 CONH2 3-pyridyl 2-methyl-1-imidazolyl 1075CONH2 3-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 1076 CONH23-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1077 CONH23-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1078 CONH2 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1079 CONH2 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1080 CONH2 2-pyrimidyl2-(aminosulfonyl)phenyl 1081 CONH2 2-pyrimidyl2-(methylaminosulfonyl)phenyl 1082 CONH2 2-pyrimidyl1-pyrrolidinocarbonyl 1083 CONH2 2-pyrimidyl 2-(methylsulfonyl)phenyl1084 CONH2 2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 1085 CONH22-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 1086 CONH2 2-pyrimidyl1-methyl-2-imidazolyl 1087 CONH2 2-pyrimidyl 2-methyl-1-imidazolyl 1088CONH2 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 1089 CONH22-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1090 CONH22-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1091 CONH2 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1092 CONH2 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl) methyl)phenyl 1093 CONH2 5-pyrimidyl2-(aminosulfonyl)phenyl 1094 CONH2 5-pyrimidyl2-(methylaminosulfonyl)phenyl 1095 CONH2 5-pyrimidyl1-pyrrolidinocarbonyl 1096 CONH2 5-pyrimidyl 2-(methylsulfonyl)phenyl1097 CONH2 5-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 1098 CONH25-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 1099 CONH2 5-pyrimidyl1-methyl-2-imidazolyl 1100 CONH2 5-pyrimidyl 2-methyl-1-imidazolyl 1101CONH2 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 1102 CONH25-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1103 CONH25-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1104 CONH2 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1105 CONH2 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl) - methyl)phenyl 1106 CONH2 2-F-phenyl2-(aminosulfonyl)phenyl 1107 CONH2 2-F-phenyl2-(methylaminosulfonyl)phenyl 1108 CONH2 2-F-phenyl1-pyrrolidinocarbonyl 1109 CONH2 2-F-phenyl 2-(methylsulfonyl)phenyl1110 CONH2 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1111 CONH22-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1112 CONH2 2-F-phenyl1-methyl-2-imidazolyl 1113 CONH2 2-F-phenyl 2-methyl-1-imidazolyl 1114CONH2 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1115 CONH22-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1116 CONH22-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1117 CONH2 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1118 CONH2 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1119 CONH2 2-F-phenyl2-(aminosulfonyl)phenyl 1120 CONH2 2-F-phenyl2-(methylaminosulfonyl)phenyl 1121 CONH2 2-F-phenyl1-pyrrolidinocarbonyl 1122 CONH2 2-F-phenyl 2-(methylsulfonyl)phenyl1123 CONH2 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1124 CONH22-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1125 CONH2 2-F-phenyl1-methyl-2-imidazolyl 1126 CONH2 2-F-phenyl 2-methyl-1-imidazolyl 1127CONH2 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1128 CONH22-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1129 CONH22-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1130 CONH2 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1131 CONH2 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1132 CONH2 2,6-diF-phenyl2-(aminosulfonyl)phenyl 1133 CONH2 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 1134 CONH2 2,6-diF-phenyl1-pyrrolidinocarbonyl 1135 CONH2 2,6-diF-phenyl 2-(methylsulfonyl)phenyl1136 CONH2 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1137 CONH22,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1138 CONH2 2,6-diF-phenyl1-methyl-2-imidazolyl 1139 CONH2 2,6-diF-phenyl 2-methyl-1-imidazolyl1140 CONH2 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1141CONH2 2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1142CONH2 2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1143 CONH22,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 1144 CONH22,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1145 CNphenyl 2-(aminosulfonyl)phenyl 1146 CN phenyl2-(methylaminosulfonyl)phenyl 1147 CN phenyl 1-pyrrolidinocarbonyl 1148CN phenyl 2-(methylsulfonyl)phenyl 1149 CN phenyl 2-(N,N-dimethylaminomethyl)phenyl 1150 CN phenyl 2-(N-pyrrolidinylmethyl)phenyl1151 CN phenyl 1-methyl-2-imidazolyl 1152 CN phenyl2-methyl-1-imidazolyl 1153 CN phenyl 2-(dimethylaminomethyl)-1-imidazolyl 1154 CN phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl1155 CN phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1156 CN phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1157 CN phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1158 CN 2-pyridyl2-(aminosulfonyl)phenyl 1159 CN 2-pyridyl 2-(methylaminosulfonyl)phenyl1160 CN 2-pyridyl 1-pyrrolidinocarbonyl 1161 CN 2-pyridyl2-(methylsulfonyl)phenyl 1162 CN 2-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 1163 CN 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 1164 CN 2-pyridyl 1-methyl-2-imidazolyl1165 CN 2-pyridyl 2-methyl-1-imidazolyl 1166 CN 2-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 1167 CN 2-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1168 CN 2-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1169 CN 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1170 CN 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1171 CN 3-pyridyl2-(aminosulfonyl)phenyl 1172 CN 3-pyridyl 2-(methylaminosulfonyl)phenyl1173 CN 3-pyridyl 1-pyrrolidinocarbonyl 1174 CN 3-pyridyl2-(methylsulfonyl)phenyl 1175 CN 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 1176 CN 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 1177 CN 3-pyridyl 1-methyl-2-imidazolyl1178 CN 3-pyridyl 2-methyl-1-imidazolyl 1179 CN 3-pyridyl2-(dimethylaminomethyl)-1- imidazolyl 1180 CN 3-pyridyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1181 CN 3-pyridyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1182 CN 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1183 CN 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1184 CN 2-pyrimidyl2-(aminosulfonyl)phenyl 1185 CN 2-pyrimidyl2-(methylaminosulfonyl)phenyl 1186 CN 2-pyrimidyl 1-pyrrolidinocarbonyl1187 CN 2-pyrimidyl 2-(methylsulfonyl)phenyl 1188 CN 2-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 1189 CN 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 1190 CN 2-pyrimidyl 1-methyl-2-imidazolyl1191 CN 2-pyrimidyl 2-methyl-1-imidazolyl 1192 CN 2-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 1193 CN 2-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1194 CN 2-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1195 CN 2-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1196 CN 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1197 CN 5-pyrimidyl2-(aminosulfonyl)phenyl 1198 CN 5-pyrimidyl2-(methylaminosulfonyl)phenyl 1199 CN 5-pyrimidyl 1-pyrrolidinocarbonyl1200 CN 5-pyrimidyl 2-(methylsulfonyl)phenyl 1201 CN 5-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl 1202 CN 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 1203 CN 5-pyrimidyl 1-methyl-2-imidazolyl1204 CN 5-pyrimidyl 2-methyl-1-imidazolyl 1205 CN 5-pyrimidyl2-(dimethylaminomethyl)-1- imidazolyl 1206 CN 5-pyrimidyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1207 CN 5-pyrimidyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1208 CN 5-pyrimidyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1209 CN 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1210 CN 2-F-phenyl2-(aminosulfonyl)phenyl 1211 CN 2-F-phenyl 2-(methylaminosulfonyl)phenyl1212 CN 2-F-phenyl 1-pyrrolidinocarbonyl 1213 CN 2-F-phenyl2-(methylsulfonyl)phenyl 1214 CN 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 1215 CN 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 1216 CN 2-F-phenyl 1-methyl-2-imidazolyl1217 CN 2-F-phenyl 2-methyl-1-imidazolyl 1218 CN 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 1219 CN 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1220 CN 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1221 CN 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1222 CN 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1223 CN 2-F-phenyl2-(aminosulfonyl)phenyl 1224 CN 2-F-phenyl 2-(methylaminosulfonyl)phenyl1225 CN 2-F-phenyl 1-pyrrolidinocarbonyl 1226 CN 2-F-phenyl2-(methylsulfonyl)phenyl 1227 CN 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 1228 CN 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 1229 CN 2-F-phenyl 1-methyl-2-imidazolyl1230 CN 2-F-phenyl 2-methyl-1-imidazolyl 1231 CN 2-F-phenyl2-(dimethylaminomethyl)-1- imidazolyl 1232 CN 2-F-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1233 CN 2-F-phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1234 CN 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1235 CN 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1236 CN 2,6-diF-phenyl2-(aminosulfonyl)phenyl 1237 CN 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 1238 CN 2,6-diF-phenyl1-pyrrolidinocarbonyl 1239 CN 2,6-diF-phenyl 2-(methylsulfonyl)phenyl1240 CN 2,6-diF-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1241 CN2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1242 CN 2,6-diF-phenyl1-methyl-2-imidazolyl 1243 CN 2,6-diF-phenyl 2-methyl-1-imidazolyl 1244CN 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1245 CN2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1246 CN2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1247 CN2,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 1248 CN2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1249 CH2NH2phenyl 2-(aminosulfonyl)phenyl 1250 CH2NH2 phenyl2-(methylaminosulfonyl)phenyl 1251 CH2NH2 phenyl 1-pyrrolidinocarbonyl1252 CH2NH2 phenyl 2-(methylsulfonyl)phenyl 1253 CH2NH2 phenyl 2-(N,N-dimethylaminomethyl)phenyl 1254 CH2NH2 phenyl2-(N-pyrrolidinylmethyl)phenyl 1255 CH2NH2 phenyl 1-methyl-2-imidazolyl1256 CH2NH2 phenyl 2-methyl-1-imidazolyl 1257 CH2NH2 phenyl2-(dimethylaminomethyl)-1- imidazolyl 1258 CH2NH2 phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1259 CH2NH2 phenyl2-(N-(cyclobutyl)- aminomethyl)phenyl 1260 CH2NH2 phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1261 CH2NH2 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1262 CH2NH2 2-pyridyl2-(aminosulfonyl)phenyl 1263 CH2NH2 2-pyridyl2-(methylaminosulfonyl)phenyl 1264 CH2NH2 2-pyridyl1-pyrrolidinocarbonyl 1265 CH2NH2 2-pyridyl 2-(methylsulfonyl)phenyl1266 CH2NH2 2-pyridyl 2-(N,N- dimethylaminomethyl)phenyl 1267 CH2NH22-pyridyl 2-(N-pyrrolidinylmethyl)phenyl 1268 CH2NH2 2-pyridyl1-methyl-2-imidazolyl 1269 CH2NH2 2-pyridyl 2-methyl-1-imidazolyl 1270CH2NH2 2-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 1271 CH2NH22-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1272 CH2NH22-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1273 CH2NH2 2-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1274 CH2NH2 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1275 CH2NH2 3-pyridyl2-(aminosulfonyl)phenyl 1276 CH2NH2 3-pyridyl2-(methylaminosulfonyl)phenyl 1277 CH2NH2 3-pyridyl1-pyrrolidinocarbonyl 1278 CH2NH2 3-pyridyl 2-(methylsulfonyl)phenyl1279 CH2NH2 3-pyridyl 2-(N,N- dimethylaminomethyl)phenyl 1280 CH2NH23-pyridyl 2-(N-pyrrolidinylmethyl)phenyl 1281 CH2NH2 3-pyridyl1-methyl-2-imidazolyl 1282 CH2NH2 3-pyridyl 2-methyl-1-imidazolyl 1283CH2NH2 3-pyridyl 2-(dimethylaminomethyl)-1- imidazolyl 1284 CH2NH23-pyridyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1285 CH2NH23-pyridyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1286 CH2NH2 3-pyridyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1287 CH2NH2 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1288 CH2NH2 2-pyrimidyl2-(aminosulfonyl)phenyl 1289 CH2NH2 2-pyrimidyl2-(methylaminosulfonyl)phenyl 1290 CH2NH2 2-pyrimidyl1-pyrrolidinocarbonyl 1291 CH2NH2 2-pyrimidyl 2-(methylsulfonyl)phenyl1292 CH2NH2 2-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 1293 CH2NH22-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 1294 CH2NH2 2-pyrimidyl1-methyl-2-imidazolyl 1295 CH2NH2 2-pyrimidyl 2-methyl-1-imidazolyl 1296CH2NH2 2-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 1297 CH2NH22-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1298 CH2NH22-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1299 CH2NH22-pyrimidyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 1300 CH2NH22-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1301 CH2NH25-pyrimidyl 2-(aminosulfonyl)phenyl 1302 CH2NH2 5-pyrimidyl2-(methylaminosulfonyl)phenyl 1303 CH2NH2 5-pyrimidyl1-pyrrolidinocarbonyl 1304 CH2NH2 5-pyrimidyl 2-(methylsulfonyl)phenyl1305 CH2NH2 5-pyrimidyl 2-(N,N- dimethylaminomethyl)phenyl 1306 CH2NH25-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl 1307 CH2NH2 5-pyrimidyl1-methyl-2-imidazolyl 1308 CH2NH2 5-pyrimidyl 2-methyl-1-imidazolyl 1309CH2NH2 5-pyrimidyl 2-(dimethylaminomethyl)-1- imidazolyl 1310 CH2NH25-pyrimidyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1311 CH2NH25-pyrimidyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1312 CH2NH25-pyrimidyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 1313 CH2NH25-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1314 CH2NH22-F-phenyl 2-(aminosulfonyl)phenyl 1315 CH2NH2 2-F-phenyl2-(methylaminosulfonyl)phenyl 1316 CH2NH2 2-F-phenyl1-pyrrolidinocarbonyl 1317 CH2NH2 2-F-phenyl 2-(methylsulfonyl)phenyl1318 CH2NH2 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1319 CH2NH22-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1320 CH2NH2 2-F-phenyl1-methyl-2-imidazolyl 1321 CH2NH2 2-F-phenyl 2-methyl-1-imidazolyl 1322CH2NH2 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1323 CH2NH22-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1324 CH2NH22-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1325 CH2NH2 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1326 CH2NH2 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1327 CH2NH2 2-F-phenyl2-(aminosulfonyl)phenyl 1328 CH2NH2 2-F-phenyl2-(methylaminosulfonyl)phenyl 1329 CH2NH2 2-F-phenyl1-pyrrolidinocarbonyl 1330 CH2NH2 2-F-phenyl 2-(methylsulfonyl)phenyl1331 CH2NH2 2-F-phenyl 2-(N,N- dimethylaminomethyl)phenyl 1332 CH2NH22-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl 1333 CH2NH2 2-F-phenyl1-methyl-2-imidazolyl 1334 CH2NH2 2-F-phenyl 2-methyl-1-imidazolyl 1335CH2NH2 2-F-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1336 CH2NH22-F-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1337 CH2NH22-F-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1338 CH2NH2 2-F-phenyl2-(N-(cyclopentyl)- aminomethyl)phenyl 1339 CH2NH2 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1340 CH2NH2 2,6-diF-phenyl2-(aminosulfonyl)phenyl 1341 CH2NH2 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 1342 CH2NH2 2,6-diF-phenyl1-pyrrolidinocarbonyl 1343 CH2NH2 2,6-diF-phenyl2-(methylsulfonyl)phenyl 1344 CH2NH2 2,6-diF-phenyl 2-(N,N-dimethylaminomethyl)phenyl 1345 CH2NH2 2,6-diF-phenyl2-(N-pyrrolidinylmethyl)phenyl 1346 CH2NH2 2,6-diF-phenyl1-methyl-2-imidazolyl 1347 CH2NH2 2,6-diF-phenyl 2-methyl-1-imidazolyl1348 CH2NH2 2,6-diF-phenyl 2-(dimethylaminomethyl)-1- imidazolyl 1349CH2NH2 2,6-diF-phenyl 2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 1350CH2NH2 2,6-diF-phenyl 2-(N-(cyclobutyl)- aminomethyl)phenyl 1351 CH2NH22,6-diF-phenyl 2-(N-(cyclopentyl)- aminomethyl)phenyl 1352 CH2NH22,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 1353 CH2NH—phenyl 2-(aminosulfonyl)phenyl SO2CH3 1354 CH2NH— phenyl2-(methylaminosulfonyl)phenyl SO2CH3 1355 CH2NH— phenyl1-pyrrolidinocarbonyl SO2CH3 1356 CH2NH— phenyl 2-(methylsulfonyl)phenylSO2CH3 1357 CH2NH— phenyl 2-(N,N- SO2CH3 dimethylaminomethyl)phenyl 1358CH2NH— phenyl 2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1359 CH2NH— phenyl1-methyl-2-imidazolyl SO2CH3 1360 CH2NH— phenyl 2-methyl-1-imidazolylSO2CH3 1361 CH2NH— phenyl 2-(dimethylaminomethyl)-1- SO2CH3 imidazolyl1362 CH2NH— phenyl 2-(N-(cyclopropyl- SO2CH3 methyl)aminomethyl)phenyl1363 CH2NH— phenyl 2-(N-(cyclobutyl)- SO2CH3 aminomethyl)phenyl 1364CH2NH— phenyl 2-(N-(cyclopentyl)- SO2CH3 aminomethyl)phenyl 1365 CH2NH—phenyl 2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl 1366 CH2NH—2-pyridyl 2-(aminosulfonyl)phenyl SO2CH3 1367 CH2NH— 2-pyridyl2-(methylaminosulfonyl)phenyl SO2CH3 1368 CH2NH— 2-pyridyl1-pyrrolidinocarbonyl SO2CH3 1369 CH2NH— 2-pyridyl2-(methylsulfonyl)phenyl SO2CH3 1370 CH2NH— 2-pyridyl 2-(N,N- SO2CH3dimethylaminomethyl)phenyl SO2CH3 1371 CH2NH— 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1372 CH2NH— 2-pyridyl1-methyl-2-imidazolyl SO2CH3 1373 CH2NH— 2-pyridyl 2-methyl-1-imidazolylSO2CH3 1374 CH2NH— 2-pyridyl 2-(dimethylaminomethyl)-1- SO2CH3imidazolyl 1375 CH2NH— 2-pyridyl 2-(N-(cyclopropyl- SO2CH3methyl)aminomethyl)phenyl 1376 CH2NH— 2-pyridyl 2-(N-(cyclobutyl)-SO2CH3 aminomethyl)phenyl 1377 CH2NH— 2-pyridyl 2-(N-(cyclopentyl)-SO2CH3 aminomethyl)phenyl 1378 CH2NH— 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl 1379 CH2NH— 3-pyridyl2-(aminosulfonyl)phenyl SO2CH3 1380 CH2NH— 3-pyridyl2-(methylaminosulfonyl)phenyl SO2CH3 1381 CH2NH— 3-pyridyl1-pyrrolidinocarbonyl SO2CH3 1382 CH2NH— 3-pyridyl2-(methylsulfonyl)phenyl SO2CH3 1383 CH2NH— 3-pyridyl 2-(N,N- SO2CH3dimethylaminomethyl)phenyl 1384 CH2NH— 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1385 CH2NH— 3-pyridyl1-methyl-2-imidazolyl SO2CH3 1386 CH2NH— 3-pyridyl 2-methyl-1-imidazolylSO2CH3 1387 CH2NH— 3-pyridyl 2-(dimethylaminomethyl)-1- SO2CH3imidazolyl 1388 CH2NH— 3-pyridyl 2-(N-(cyclopropyl- SO2CH3methyl)aminomethyl)phenyl 1389 CH2NH— 3-pyridyl 2-(N-(cyclobutyl)-SO2CH3 aminomethyl)phenyl 1390 CH2NH— 3-pyridyl 2-(N-(cyclopentyl)-SO2CH3 aminomethyl)phenyl 1391 CH2NH— 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl 1392 CH2NH—2-pyrimidyl 2-(aminosulfonyl)phenyl SO2CH3 1393 CH2NH— 2-pyrimidyl2-(methylaminosulfonyl)phenyl SO2CH3 1394 CH2NH— 2-pyrimidyl1-pyrrolidinocarbonyl SO2CH3 1395 CH2NH— 2-pyrimidyl2-(methylsulfonyl)phenyl SO2CH3 1396 CH2NH— 2-pyrimidyl 2-(N,N- SO2CH3dimethylaminomethyl)phenyl 1397 CH2NH— 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1398 CH2NH— 2-pyrimidyl1-methyl-2-imidazolyl SO2CH3 1399 CH2NH— 2-pyrimidyl2-methyl-1-imidazolyl SO2CH3 1400 CH2NH— 2-pyrimidyl2-(dimethylaminomethyl)-1- SO2CH3 imidazolyl 1401 CH2NH— 2-pyrimidyl2-(N-(cyclopropyl- SO2CH3 methyl)aminomethyl)phenyl 1402 CH2NH—2-pyrimidyl 2-(N-(cyclobutyl)- SO2CH3 aminomethyl)phenyl 1403 CH2NH—2-pyrimidyl 2-(N-(cyclopentyl)- SO2CH3 aminomethyl)phenyl 1404 CH2NH—2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl 1405CH2NH— 5-pyrimidyl 2-(aminosulfonyl)phenyl SO2CH3 1406 CH2NH—5-pyrimidyl 2-(methylaminosulfonyl)phenyl SO2CH3 1407 CH2NH— 5-pyrimidyl1-pyrrolidinocarbonyl SO2CH3 1408 CH2NH— 5-pyrimidyl2-(methylsulfonyl)phenyl SO2CH3 1409 CH2NH— 5-pyrimidyl 2-(N,N- SO2CH3dimethylaminomethyl)phenyl 1410 CH2NH— 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1411 CH2NH— 5-pyrimidyl1-methyl-2-imidazolyl SO2CH3 1412 CH2NH— 5-pyrimidyl2-methyl-1-imidazolyl SO2CH3 1413 CH2NH— 5-pyrimidyl2-(dimethylaminomethyl)-1- SO2CH3 imidazolyl 1414 CH2NH— 5-pyrimidyl2-(N-(cyclopropyl- SO2CH3 methyl)aminomethyl)phenyl 1415 CH2NH—5-pyrimidyl 2-(N-(cyclobutyl)- SO2CH3 aminomethyl)phenyl 1416 CH2NH—5-pyrimidyl 2-(N-(cyclopentyl)- SO2CH3 aminomethyl)phenyl 1417 CH2NH—5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl 1418CH2NH— 2-Cl-phenyl 2-(aminosulfonyl)phenyl SO2CH3 1419 CH2NH—2-Cl-phenyl 2-(methylaminosulfonyl)phenyl SO2CH3 1420 CH2NH— 2-Cl-phenyl1-pyrrolidinocarbonyl SO2CH3 1421 CH2NH— 2-Cl-phenyl2-(methylsulfonyl)phenyl SO2CH3 1422 CH2NH— 2-Cl-phenyl 2-(N,N- SO2CH3dimethylaminomethyl)phenyl 1423 CH2NH— 2-Cl-phenyl2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1424 CH2NH— 2-Cl-phenyl1-methyl-2-imidazolyl SO2CH3 1425 CH2NH— 2-Cl-phenyl2-methyl-1-imidazolyl SO2CH3 1426 CH2NH— 2-Cl-phenyl2-(dimethylaminomethyl)-1- SO2CH3 imidazolyl 1427 CH2NH— 2-Cl-phenyl2-(N-(cyclopropyl- SO2CH3 methyl)aminomethyl)phenyl 1428 CH2NH—2-Cl-phenyl 2-(N-(cyclobutyl)- SO2CH3 aminomethyl)phenyl 1429 CH2NH—2-Cl-phenyl 2-(N-(cyclopentyl)- SO2CH3 aminomethyl)phenyl 1430 CH2NH—2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl 1431CH2NH— 2-F-phenyl 2-(aminosulfonyl)phenyl SO2CH3 1432 CH2NH— 2-F-phenyl2-(methylaminosulfonyl)phenyl SO2CH3 1433 CH2NH— 2-F-phenyl1-pyrrolidinocarbonyl SO2CH3 1434 CH2NH— 2-F-phenyl2-(methylsulfonyl)phenyl SO2CH3 1435 CH2NH— 2-F-phenyl 2-(N,N- SO2CH3dimethylaminomethyl)phenyl 1436 CH2NH— 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1437 CH2NH— 2-F-phenyl1-methyl-2-imidazolyl SO2CH3 1438 CH2NH— 2-F-phenyl2-methyl-1-imidazolyl SO2CH3 1439 CH2NH— 2-F-phenyl2-(dimethylaminomethyl)-1- SO2CH3 imidazolyl 1440 CH2NH— 2-F-phenyl2-(N-(cyclopropyl- SO2CH3 methyl)aminomethyl)phenyl 1441 CH2NH—2-F-phenyl 2-(N-(cyclobutyl)- SO2CH3 aminomethyl)phenyl 1442 CH2NH—2-F-phenyl 2-(N-(cyclopentyl)- SO2CH3 aminomethyl)phenyl 1443 CH2NH—2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl 1444CH2NH— 2,6-diF-phenyl 2-(aminosulfonyl)phenyl SO2CH3 1445 CH2NH—2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl SO2CH3 1446 CH2NH—2,6-diF-phenyl 1-pyrrolidinocarbonyl SO2CH3 1447 CH2NH— 2,6-diF-phenyl2-(methylsulfonyl)phenyl SO2CH3 1448 CH2NH— 2,6-diF-phenyl 2-(N,N-SO2CH3 dimethylaminomethyl)phenyl 1449 CH2NH— 2,6-diF-phenyl2-(N-pyrrolidinylmethyl)phenyl SO2CH3 1450 CH2NH— 2,6-diF-phenyl1-methyl-2-imidazolyl SO2CH3 1451 CH2NH— 2,6-diF-phenyl2-methyl-1-imidazolyl SO2CH3 1452 CH2NH— 2,6-diF-phenyl2-(dimethylaminomethyl)-1- SO2CH3 imidazolyl 1453 CH2NH— 2,6-diF-phenyl2-(N-(cyclopropyl- SO2CH3 methyl)aminomethyl)phenyl 1454 CH2NH—2,6-diF-phenyl 2-(N-(cyclobutyl)- SO2CH3 aminomethyl)phenyl 1455 CH2NH—2,6-diF-phenyl 2-(N-(cyclopentyl)- SO2CH3 aminomethyl)phenyl 1456 CH2NH—2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)- SO2CH3 methyl)phenyl

TABLE 2

Z is N;

Z is N;

Z is N;

Z is N;

Z is N;

Z¹ is O;

Z¹ is O;

Z¹ is O;

Z¹ is O;

Z¹ is O;

Z¹ is S;

Z¹ is S;

Z¹ is S;

Z¹ is S;

Z¹ is S;

Z¹ is NH;

Z¹ is NH;

Z¹ is NH;

Z¹ is NH;

Z¹ is NH;

Z¹ is NCH₃;

Z¹ is NCH₃;

Z¹ is NCH₃;

Z¹ is NCH₃;

Z¹ is NCH₃;

-   G is selected from:    -   4-(methoxy)phenyl;    -   2-(aminomethyl)phenyl;    -   3-(aminomethyl)phenyl;    -   2-(aminomethyl)-3-fluorophenyl;    -   2-(aminomethyl)-4-fluorophenyl;    -   2-(aminomethyl)-5-fluorophenyl;    -   2-(aminomethyl)-6-fluorophenyl;    -   3-amino-phthalazin-5-yl;    -   3-amino-phthalazin-6-yl;    -   1-aminoisoquinolin-6-yl;    -   1-aminoisoquinolin-7-yl;    -   4-aminoquinazol-6-yl;    -   4-aminoquinazol-7-yl;    -   3-aminobenzisoxazol-5-yl;    -   3-aminobenzisoxazol-6-yl;    -   3-aminoisobenzazol-5-yl; and,    -   3-aminoisobenzazaol-6-yl;

Ex # A B  1 phenyl 2-(aminosulfonyl)phenyl  2 phenyl2-(methylaminosulfonyl)phenyl  3 phenyl 1-pyrrolidinocarbonyl  4 phenyl2-(methylsulfonyl)phenyl  5 phenyl 2-(N,N-dimethylaminomethyl)phenyl  6phenyl 2-(N-pyrrolidinylmethyl)phenyl  7 phenyl 1-methyl-2-imidazolyl  8phenyl 2-methyl-1-imidazolyl  9 phenyl2-(dimethylaminomethyl)-1-imidazolyl 10 phenyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 11 phenyl 2-(N-(cyclobutyl)-aminomethyl)phenyl12 phenyl 2-(N-(cyclopentyl)-aminomethyl)phenyl 13 phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 14 2-pyridyl2-(aminosulfonyl)phenyl 15 2-pyridyl 2-(methylaminosulfonyl)phenyl 162-pyridyl 1-pyrrolidinocarbonyl 17 2-pyridyl 2-(methylsulfonyl)phenyl 182-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 19 2-pyridyl2-(N-pyrrolidinylmethyl)phenyl 20 2-pyridyl 1-methyl-2-imidazolyl 212-pyridyl 2-methyl-1-imidazolyl 22 2-pyridyl2-(dimethylaminomethyl)-1-imidazolyl 23 2-pyridyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 24 2-pyridyl2-(N-(cyclobutyl)-aminomethyl)phenyl 25 2-pyridyl2-(N-(cyclopentyl)-aminomethyl)phenyl 26 2-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 27 3-pyridyl2-(aminosulfonyl)phenyl 28 3-pyridyl 2-(methylaminosulfonyl)phenyl 293-pyridyl 1-pyrrolidinocarbonyl 30 3-pyridyl 2-(methylsulfonyl)phenyl 313-pyridyl 2-(N,N-dimethylaminomethyl)phenyl 32 3-pyridyl2-(N-pyrrolidinylmethyl)phenyl 33 3-pyridyl 1-methyl-2-imidazolyl 343-pyridyl 2-methyl-1-imidazolyl 35 3-pyridyl2-(dimethylaminomethyl)-1-imidazolyl 36 3-pyridyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 37 3-pyridyl2-(N-(cyclobutyl)-aminomethyl)phenyl 38 3-pyridyl2-(N-(cyclopentyl)-aminomethyl)phenyl 39 3-pyridyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 40 2-pyrimidyl2-(aminosulfonyl)phenyl 41 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 422-pyrimidyl 1-pyrrolidinocarbonyl 43 2-pyrimidyl2-(methylsulfonyl)phenyl 44 2-pyrimidyl2-(N,N-dimethylaminomethyl)phenyl 45 2-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 46 2-pyrimidyl 1-methyl-2-imidazolyl 472-pyrimidyl 2-methyl-1-imidazolyl 48 2-pyrimidyl2-(dimethylaminomethyl)-1-imidazolyl 49 2-pyrimidyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 50 2-pyrimidyl2-(N-(cyclobutyl)-aminomethyl)phenyl 51 2-pyrimidyl2-(N-(cyclopentyl)-aminomethyl)phenyl 52 2-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 53 5-pyrimidyl2-(aminosulfonyl)phenyl 54 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 555-pyrimidyl 1-pyrrolidinocarbonyl 56 5-pyrimidyl2-(methylsulfonyl)phenyl 57 5-pyrimidyl2-(N,N-dimethylaminomethyl)phenyl 58 5-pyrimidyl2-(N-pyrrolidinylmethyl)phenyl 59 5-pyrimidyl 1-methyl-2-imidazolyl 605-pyrimidyl 2-methyl-1-imidazolyl 61 5-pyrimidyl2-(dimethylaminomethyl)-1-imidazolyl 62 5-pyrimidyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 63 5-pyrimidyl2-(N-(cyclobutyl)-aminomethyl)phenyl 64 5-pyrimidyl2-(N-(cyclopentyl)-aminomethyl)phenyl 65 5-pyrimidyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 66 2-Cl-phenyl2-(aminosulfonyl)phenyl 67 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 682-Cl-phenyl 1-pyrrolidinocarbonyl 69 2-Cl-phenyl2-(methylsulfonyl)phenyl 70 2-Cl-phenyl2-(N,N-dimethylaminomethyl)phenyl 71 2-Cl-phenyl2-(N-pyrrolidinylmethyl)phenyl 72 2-Cl-phenyl 1-methyl-2-imidazolyl 732-Cl-phenyl 2-methyl-1-imidazolyl 74 2-Cl-phenyl2-(dimethylaminomethyl)-1-imidazolyl 75 2-Cl-phenyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 76 2-Cl-phenyl2-(N-(cyclobutyl)-aminomethyl)phenyl 77 2-Cl-phenyl2-(N-(cyclopentyl)-aminomethyl)phenyl 78 2-Cl-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 79 2-F-phenyl2-(aminosulfonyl)phenyl 80 2-F-phenyl 2-(methylaminosulfonyl)phenyl 812-F-phenyl 1-pyrrolidinocarbonyl 82 2-F-phenyl 2-(methylsulfonyl)phenyl83 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl 84 2-F-phenyl2-(N-pyrrolidinylmethyl)phenyl 85 2-F-phenyl 1-methyl-2-imidazolyl 862-F-phenyl 2-methyl-1-imidazolyl 87 2-F-phenyl2-(dimethylaminomethyl)-1-imidazolyl 88 2-F-phenyl 2-(N-(cyclopropyl-methyl)aminomethyl)phenyl 89 2-F-phenyl2-(N-(cyclobutyl)-aminomethyl)phenyl 90 2-F-phenyl2-(N-(cyclopentyl)-aminomethyl)phenyl 91 2-F-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl 92 2,6-diF-phenyl2-(aminosulfonyl)phenyl 93 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl94 2,6-diF-phenyl 1-pyrrolidinocarbonyl 95 2,6-diF-phenyl2-(methylsulfonyl)phenyl 96 2,6-diF-phenyl2-(N,N-dimethylaminomethyl)phenyl 97 2,6-diF-phenyl2-(N-pyrrolidinylmethyl)phenyl 98 2,6-diF-phenyl 1-methyl-2-imidazolyl99 2,6-diF-phenyl 2-methyl-1-imidazolyl 100  2,6-diF-phenyl2-(dimethylaminomethyl)-1-imidazolyl 101  2,6-diF-phenyl2-(N-(cyclopropyl- methyl)aminomethyl)phenyl 102  2,6-diF-phenyl2-(N-(cyclobutyl)-aminomethyl)phenyl 103  2,6-diF-phenyl2-(N-(cyclopentyl)-aminomethyl)phenyl 104  2,6-diF-phenyl2-(N-(3-hydroxypyrrolidinyl)- methyl)phenyl

UTILITY

The compounds of this invention are useful as anticoagulants for thetreatment or prevention of thromboembolic disorders in mammals. The term“thromboembolic disorders” as used herein includes arterial or venouscardiovascular or cerebrovascular thromboembolic disorders, including,for example, unstable angina, first or recurrent myocardial infarction,ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolisms, and pulmonaryembolisms. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors offactor Xa was determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absenceand presence of compounds of the present invention. Hydrolysis of thesubstrate resulted in the release of pNA, which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,Km, for substrate hydrolysis was determined at 25° C. using the methodof Lineweaver and Burk. Values of K_(i) were determined by allowing0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend,Ind.) to react with the substrate (0.20 mM-1 mM) in the presence ofinhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25-30 minutes. The following relationship was used to calculateK_(i) values:(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))where:

-   -   v_(o) is the velocity of the control in the absence of        inhibitor;    -   v_(s) is the velocity in the presence of inhibitor;    -   I is the concentration of inhibitor;    -   K_(i) is the dissociation constant of the enzyme:inhibitor        complex;    -   S is the concentration of substrate;    -   K_(m) is the Michaelis constant.        Using the methodology described above, a number of compounds of        the present invention were found to exhibit a K_(i) of ≦10 μM,        thereby confirming the utility of the compounds of the present        invention as effective Xa inhibitors.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2-3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing that contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After forty minutes, the shunt is disconnectedand the silk thread covered with thrombus is weighed. Test agents orvehicle will be given (i.v., i.p., s.c., or orally) prior to the openingof the AV shunt. The percentage inhibition of thrombus formation isdetermined for each treatment group. The ID50 values (dose whichproduces 50% inhibition of thrombus formation) are estimated by linearregression.

The compounds of formula (I) may also be useful as inhibitors of serineproteases, notably human thrombin, plasma kallikrein and plasmin.Because of their inhibitory action, these compounds are indicated foruse in the prevention or treatment of physiological reactions, bloodcoagulation and inflammation, catalyzed by the aforesaid class ofenzymes. Specifically, the compounds have utility as drugs for thetreatment of diseases arising from elevated thrombin activity such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

Some compounds of the present invention were shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 1990, 265, 18289-18297,herein incorporated by reference. In these assays, thrombin-mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) was monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,was incubated with various substrate concentrations ranging from 0.20 to0.02 mM. After 25 to 30 minutes of incubation, thrombin activity wasassayed by monitoring the rate of increase in absorbance at 405 nm thatarises owing to substrate hydrolysis. Inhibition constants were derivedfrom reciprocal plots of the reaction velocity as a function ofsubstrate concentration using the standard method of Lineweaver andBurk. Using the methodology described above, some compounds of thisinvention were evaluated and found to exhibit a K_(i) of less than 10μm, thereby confirming the utility of the compounds of the presentinvention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

By “administered in combination” or “combination therapy” it is meantthat the compound of Formula I and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component maybe administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect. Otheranticoagulant agents (or coagulation inhibitory agents) that may be usedin combination with the compounds of this invention include warfarin andheparin, as well as other factor Xa inhibitors such as those describedin the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicyclic acid or ASA), and piroxicam are preferred. Othersuitable anti-platelet agents include ticlopidine, includingpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine isalso a preferred compound since it is known to be gentle on thegastro-intestinal tract in use. Still other suitable platelet inhibitoryagents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonistsand thromboxane-A2-synthetase inhibitors, as well as pharmaceuticallyacceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin and argatroban, includingpharmaceutically acceptable salts and prodrugs thereof. Boroargininederivatives and boropeptides include N-acetyl and peptide derivatives ofboronic acid, such as C-terminal a-aminoboronic acid derivatives oflysine, ornithine, arginine, homoarginine and correspondingisothiouronium analogs thereof. The term hirudin, as used herein,includes suitable derivatives or analogs of hirudin, referred to hereinas hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitorsinclude compounds described in Kettner et al., U.S. Pat. No. 5,187,157and European Patent is Application Publication Number 293 881 A2, thedisclosures of which are hereby incorporated herein by reference. Othersuitable boroarginine derivatives and boropeptide thrombin inhibitorsinclude those disclosed in PCT Application Publication Number 92/07869and European Patent Application Publication Number 471,651 A2, thedisclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in European Patent Application No.028,489, the disclosure of which is hereby incorporated herein byreference herein. The term urokinase, as used herein, is intended todenote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase.

Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but not in thepresence of a compound of the present invention, then one would concludefactor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with ananti-platelet agent, by way of general guidance, typically a dailydosage may be about 0.01 to 25 milligrams of the compound of Formula Iand about 50 to 150 milligrams of the anti-platelet agent, preferablyabout 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer such as a lowviscosity grade of hydroxypropylmethylcellulose (HPMC) or other appropriate materials as known in theart, in order to further separate the active components. The polymercoating serves to form an additional barrier to interaction with theother component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

1. A compound selected from the group:

or a sterioisomer or pharmaceutically acceptable salt thereof, whereincompounds of the above formulas are substituted with 0-2 R³; G is agroup of formula I or II:

ring D is selected from —(CH₂)₃—, —(CH₂)₄—, —CH₂N═CH—, —CH₂CH₂N═CH—, anda 5-6 membered aromatic system containing from 0-2 heteroatoms selectedfrom the group N, O, and S, provided that from 0-1 O and S atoms arepresent; ring D, when present, is substituted with 0-2 R; E is selectedfrom phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substitutedwith 0-1 R; R is selected from Cl, F, Br, 1, OH, C₁₋₃ alkoxy, NH₂,NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃ alkyl), and CH₂CH₂N(C₁₋₃ alkyl)₂;alternatively, ring D is absent; when ring D is absent, ring E isselected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl,and ring E is substituted with R″ and R′; R″ is selected from F, Cl, Br,I, OH, C₁₋₃ alkoxy, CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷),C(O)NR⁷RB, (CR⁸R⁹)_(t)NR⁷R⁸, SH, C₁₋₃ alkyl-S, S(O)R^(3b), S(O)₂R^(3a),S(O)₂NR²R^(2a), and OCF₃; R′ is selected from H, F, Cl, Br, I, SR³,CO₂R³, NO₂, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and(CR⁸R⁹)_(t)NR⁷R⁸; alternatively, R″ and R′ combine to formmethylenedioxy or ethylenedioxy; Z is N or CR^(1a); Z¹ is S, O, or NR³;Z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R³, andS(O)_(p)R^(3c); R^(1a) is selected from H, —(CH₂)_(r)-R¹′, —CH═CH-R¹′,NHCH₂R¹″, OCH₂R¹″, SCH₂R¹″, NH(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′,and S(CH₂)₂(CH₂)_(t)R¹′; R¹′ is selected from H, C₁₋₃ alkyl, F, Cl, Br,I, —CN, —CHO, (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c),OC(O)R², (CF₂)_(r)CO₂R²C, S(O)_(p)R^(2b), NR²(CH₂)_(r)OR²,C(═NR²C)NR²R^(2a), NR²C(O)R^(2b), NR²C(O)R³, NR²C(O)NHR^(2b),NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR²,SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclic residue substituted with0-2 R^(4a), and 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a); R″ is selected from H, CH(CH₂OR²)₂,C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), a C₃₋₆carbocyclic-CH₂— residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b); R^(2a), ateach occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b); R^(2b), ateach occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b); R^(2c), ateach occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl,benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0-2 R^(4b);alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b) and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S; R³, at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, andphenyl; A is selected from: C₃₋₁₀ carbocyclic residue substituted with0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴; B is selected from: Y, X-Y, C(═NR²)NR²R^(2a),and NR²C(═NR²)NR²R^(2a); X is selected from C₁₋₄ alkylene,—CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR¹″)-, —CR²(NR¹″R²)—,—CR²(OR²)—, —CR²(SR², —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)_(p)—,—S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—,—NR²S(O)₂CR²R^(2a), —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—,—NR²C(O), —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)-, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—,—NR²CR²R^(2a), CR²R^(2a)NR², O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y isselected from: CH₂NR²R^(2a); CH₂CH₂NR²R^(2a); C₃₋₁₀ carbocyclic residuesubstituted with 0-2 R^(4a), and 5-10 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with O₂ R^(4a); R⁴, at each occurrence, is selectedfrom H, ═O, (CH₂)_(r)OR², F, Cl, Br, 1, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c)NR²C(O)R^(2b), C(O)NR²R^(2a),NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a),NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃,NCH₂R¹″, OCH₂R¹″, SCH₂R¹″, N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, andS(CH₂)₂(CH₂)_(t)R¹′; alternatively, one R⁴ is a 5-6 membered aromaticheterocycle containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S; R^(4a), at each occurrence, is selected fromH, ═O, (CH₂)_(r)OR², (CH₂)_(r)—F, (CH₂)_(r)-Br, (CH₂)_(r)—Cl, Cl, Br, F,I, C₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R²C,NR²C(O)R^(2b), C(O)NR²R^(2a), (CH₂)_(r)N═CHOR³, C(O)NH(CH₂)₂NR²R^(2a),NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃; alternatively, one R^(4a) is a 5-6 membered aromaticheterocycle containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-1 R⁵; R^(4b), at eachoccurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a),C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)-C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, isselected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, andbenzyl substituted with 0-2 R⁶; R⁶, at each occurrence, is selected fromH, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂,NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; R⁷, ateach occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆alkylanocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl; alternatively, R⁷ and R⁸ combine to form a 5 or 6membered saturated, ring which contains from 0-1 additional heteroatomsselected from the group consisting of N, O, and S; R⁹, at eachoccurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl; n, ateach occurrence, is selected from 0, 1, 2, and 3; m, at each occurrence,is selected from 0, 1, and 2; p, at each occurrence, is selected from 0,1, and 2; r, at each occurrence, is selected from 0, 1, 2, and 3; s, ateach occurrence is selected from 0, 1, and 2; and, t, at each occurrenceis selected from 0, 1, 2, and
 3. 2. A compound of claim 1, wherein thecompound is selected from the group:

wherein compounds of the above formulas are substituted with 0-2 R³; Gis selected from the group:

A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R⁴; phenyl, piperidinyl,piperazinyl, pyridyl, pyrirnidyl, furanyl, morpholinyl, thiophenyl,pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzioidazolyl, benzoxazolyl, benzthiazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; B isselected from: Y and X-Y; X is selected from C₁₋₄ alkylene, —C(O)—,—C(═NR¹″)—, —CR²(NR¹″R²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—,—NR²C(O)—, C(O)NR²CR²R^(2a), —NR²C(O)CR²R^(2a), —CR²R^(2a)C(O)NR²—,CR²R^(2a)NR²C(O), —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a), CR²R^(2a)NR², O,CR²R^(2a)O—, and —OCR²R^(2a)—; Y is C₂NR²R^(2a) or CH₂CH₂N²R^(2a);alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems that are substituted with 0-2 R^(4a); cyclopropyl,cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl,pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyffolidinyl,oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,1,2,4 oxadiazolyl, 1,2,5 oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thliadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,11,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl,benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, and isoindazolyl; alternatively, Y is selected fromthe following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N; and, s is
 0. 3. A compound of claim2, wherein G is selected from the group:


4. A compound of claim 3, wherein: G is selected from:


5. A compound of claim 4, wherein: A is selected from phenyl, pyridyl,and pyrimidyl, and is substituted with 0-2 R⁴; and, B is selected fromX-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl,and is substituted with 0-1 R^(4a); R², at each occurrence, is selectedfrom H, CH₃, CH₂CH₃, cyclopropylmethyl, cyclobutyl, and cyclopentyl;R^(2a), at each occurrence, is H or CH₃; alternatively, R² and R^(2a),together with the atom to which they are attached, combine to formpyrrolidine substituted with O₂ R^(4b); R⁴, at each occurrence, isselected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a),and (CF₂)_(r)CF₃; R^(4a) is selected from CIA alkyl, CF₃, (CH₂)_(r)OR²,(CH₂)_(r)NR²R^(2a), S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;R^(4b), at each occurrence, is selected from H, CH₃, and OH; R⁵, at eachoccurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X isCH₂ or C(O); Y is selected from pyrrolidino and morpholino; and, r, ateach occurrence, is selected from 0, 1, and
 2. 6. A compound of claim 5,wherein: A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl,2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl,2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selectedfrom the group: 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl,1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl,2-(N,N-dimethylaminomethyl)phenyl, dimethylaminomethyl)phenyl,2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl,2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl,2-(N-(cyclopropylmethyl)aminomethyl)phenyl,2-(N-(cyclobutyl)aminomethyl)phenyl,2-(N-(cyclopentyl)aminomethyl)phenyl, and2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl.
 7. A compound of claim 1,wherein the compound is selected from:1-[4-Methoxyphenyl]-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,4-dihydropyrazolo-[4,3-d]-pyrimidine-5,7-dione;1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2′-aminosulfonyl-3-fluoro-[1,1]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one-3-carboxylicacid;1-[4-Methoxyphenyl]-3-(aminocarbonyl)₆-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-cyano-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(aminomethyl)-6-[2′-aminosulfonyl-[1,1′]-biphen-4-yl-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[4-(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-12′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-cyano-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2-fluoro-4-(2-dimethylaminomethylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[2-Aminomethylphenyl]-3-(ethoxycarbonyl)-6-[2′-methylsulfonyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]3-cyano-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-cyano-5-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[2-Aminomethylphenyl]-3-cyano-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[4-(1-methylimidazol-2′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2′-N-pyrrolidinylmethyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2′-(3-(R)-hydroxy-N-pyrrolidinylmethyl)-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-(N-formylaminomethyl)-6-[2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-hydroxymethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-(ethoxycarbonyl)-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-[(tetrazol-1-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[4-Methoxyphenyl]-3-[(tetrazol-2-yl)methyl]-5-methyl-6-[(2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-6-[2′-N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-isopropylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(4,5-dihydroimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-(cyclopropylmethyl)aminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-N-pyrrolidinylmethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[2′-(N-methyl-N-isopropyl)aminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3,5-dimethyl-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-N,N-dimethylaminomethyl-[1,1′1-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;1-3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl6-[4(2-methylimidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;1-[3-Aminobenzisoxazol-5′-yl]-3-methyl-6-[4-(2-(dimethylaminomethyl)imidazol-1′-yl)-2-fluorophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;and,1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[4-(2-(dimethylaminomethyl)imidazol-1′-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;or a pharmaceutically acceptable salt form thereof.
 8. A pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof.
 9. A pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 2 or apharmaceutically acceptable salt form thereof.
 10. A pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 3 or apharmaceutically acceptable salt form thereof.
 11. A pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 4 or apharmaceutically acceptable salt form thereof.
 12. A pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 5 or apharmaceutically acceptable salt form thereof.
 13. A pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 6 or apharmaceutically acceptable salt form thereof.
 14. A pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 7 or apharmaceutically acceptable salt form thereof.
 15. A method for treatinga thromboembolic disorder, comprising: administering to a patient inneed thereof a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt form thereof.
 16. A method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 2 or a pharmaceutically acceptable salt form thereof.
 17. Amethod for treating a thromboembolic disorder, comprising: administeringto a patient in need thereof a therapeutically effective amount of acompound of claim 3 or a pharmaceutically acceptable salt form thereof.18. A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 4 or a pharmaceutically acceptable saltform thereof.
 19. A method for treating a thromboembolic disorder,comprising: administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim 5 or a pharmaceuticallyacceptable salt form thereof.
 20. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound of claim 6 or apharmaceutically acceptable salt form thereof.
 21. A method for treatinga thromboembolic disorder, comprising: administering to a patient inneed thereof a therapeutically effective amount of a compound of claim 7or a pharmaceutically acceptable salt form thereof.